Digitized  by  tine  Internet  Arciiive 

in  2010  witii  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/studyofsomefatalOObark 


a  study  of  some  fatal 
"cases  of  malaria. 


LtBRARY 
OF  THE 

THE    PRESaVTERlAN    hq. 

LEWELLYS    F.   BARKE R ,   M .  B.,Tor..^ 

Associate  in  Anatomy,  Johns  Hopkins  University,  and  Assistant  Resident  Pathologist, 
The  Johns  Hopkins  Hospital. 


Eeprinted  from  The  Johns  Hopkins  Hospital  Beporls,  Vol.  V,  1895. 


BALTIMORE 
The  Johns  Hopkins  Press 

1895 


JOHN  MURPHY  &  CO.,  PRINTERS, 
BALTIMORE. 


A  STUDY  OF  SOME  FATAL  CASES  OF  MALARIA. 

By  LEWELLYS  F.  BARKER,  M.  B.,  TOR., 

Associate  in  Anatomy  and  Assistant  Resident  Pathologist. 

PAGE. 

I.    Introduction,  -        -        -        - 5 

II.    Case  A. — Aestivo-atjtumnal  Malaria;    Anomalous   Symptoms 

DURING  Life, 6 

III.  Case  B. — Aestivo-autumnal  Malaria  ;  Grave  Abdominal  Symp- 

toms,       --- 13 

IV.  Case  C. — Acute  Aestivo-autumnal  Malaria  ;  Death  from  Acci- 

dent ;  Acute  Necrotic  Lesions  in  Liver  and  Spleen. 
The  Relation  of  Malaria  to  Cirrhotic  Procisses,      19 

V.  Case  D. — Double  Tertian  Malarial  Infection,  Associated 
WITH  General  Streptococcus  Infection  ;  Symptoms 
OF  AN  Acute  Nephritis  with  General  Anasarca 

MANIFESTED  DURING  LiFE.  NOTE  ON  THE  CONCUR- 
RENCE OF  Bacterial  or  Protozoan  Infections  with 
Malaria,        - 29 

VI.  On  the  Unequal  Distribution  of  the  Parasites  in  the  body  in 

Malarial  Infection,    ---------47 

VII.  On  Phagocytosis  in  Malaria,         -------      54 


I. 

INTRODUCTION. 

The  material  for  the  following  study  was  derived  from  the  bodies 
of  patients  coming  to  autopsy  in  the  Pathological  Laboratory  of  the 
Johns  Hopkins  University  and  Hospital  between  1889  and  1894. 

For  the  permission  to  study  the  tissues  and  to  extract  protocols 
from  the  post-mortem  records  I  have  to  thank  Professor  W.  H.  Welch ; 
the  clinical  histories  of  the  cases  have  been  put  into  my  hands  through 
the  courtesy  of  Professor  William  Osier. 

Since  the  discovery  of  Laveran's  parasite  which  rendered  possible 
under  ordinary  circumstances  the  early  recognition  of  a  malarial 
infection  by  means  of  the  microscopical  examination  of  the  fresh  blood, 
it  has  become  a  comparatively  rare  occurrence  for  a  patient,  to  die 
of  this  disease.  The  study  of  the  pathology  of  malaria  is  consequently 
limited  to  the  few  instances  in  which  the  patients  die  from  traumatism 
or  from  some  inter-current  disease,  and  to  those  rare  cases  of  pernicious 
malarial  infection  which  terminate  fatally. 

The  tissues  from  the  cases  referred  to  in  this  paper  were  hardened  some 
in  alcohol,  some  in  Miiller's  fluid,  and  others  in  Flemming's  solution. 
For  general  study  the  tissues  fixed  in  strong  alcohol  served  best,  while 
for  the  investigation  of  certain  points  those  fixed  in  Flemming's  so- 
lution gave  excellent  results,  those  preserved  in  Miiller's  fluid  being 
the  least  satisfactory.  The  tissues  were  imbedded  in  celloidin  and  in 
paraffin.  For  staining  haematoxylin  and  eosin,  alum-cochineal,  sa- 
franin,  gentian  violet,  aqueous  magenta,  Weigert's  fibrin-stain  and 
the  triple  stain  (Ehrlich-Biondi)  were  employed,  while  for  the  study 
of  the  pigments  and  of  the  iron-containing  compounds  derived  from 
the  red  blood  corpuscles  certain  sections  were  treated  with  ammonium 
sulphide  and  others  with  hydrochloric  acid  and  ferrocyanide  of  potas- 
sium ^  (method  of  Perls). 

^  Concerning  the  reactions  for  iron  and  the  unsatisfactory  nomenclature  of  iron- 
containing  compounds,  cf.  article  by  J.  J.  Abel,  Virch.  arch.,  Bd.  120,  p.  204;  also 
articles  by  A.  B.  Macallum,  Proc.  Eoy.  Soc,  &c. 

5 


6  Leioellys  F.  Barker. 

In  order  to  determine  accurately  the  relation  of  the  parasites  and 
pigments  to  the  tissues  many  sections  both  stained  and  unstained  were 
examined  in  media  of  different  refractive  power.  For  this  purpose 
water,  glycerine,  balsam,  a  saturated  solution  of  acetate  of  potassium, 
Farrant's  medium,  and  solutions  of  chloral-hydrate  were  employed. 

The  enormous  strides  made  in  late  years  in  the  clinical  studies  of 
malaria  has  rendered  a  re-working  of  the  pathology  highly  desirable. 
The  majority  of  the  investigators  have  contented  themselves  with  the 
study  of  the  blood  taken  from  the  peripheral  circulation,  or  from  that 
obtained  from  tappings  of  the  spleen  made  during  life.  Some  how- 
ever, among  them  Bignami,  Marchiafava,  Guarnieri  and  Golgi  in 
Italy,  Metschnikoff,  Laveran,  Kelsch  and  Kiener  in  France,  and  Osier, 
Councilman,  Abbott  and  Dock  in  America  have  made  contributions 
to  our  knowledge  of  the  pathology  of  the  affection  as  it  concerns  the 
internal  organs  of  the  body. 

In  this  report  will  be  found  the  clinical  histories  of  four  cases  of 
malaria,  in  three  of  which  the  parasites  were  of  the  aestivo-autumnal 
and  in  one  of  which  they  were  of  the  tertian  type,  together  with 
a  description  of  the  pathological  findings  in  each.  As  an  appendix 
are  added  certain  observations  dealing  with  the  unequal  distribution 
of  the  parasites  in  the  body,  and  with  phagocytosis  in  malaria. 

II. 

Case  A. — Aestivo-autumnal  malaria  ;   anomalous  symptoms  during 
life. 

L.  K.,  aet.  81,  was  admitted  to  Prof.  Osier's  wards  July  18,  1889, 
complaining  of  pains  in  the  head  and  of  coldness  and  numbness  of  the 
feet  and  hands.  Had  in  earlier  life  been  always  healthy^  and  on 
admission  was  a  healthy-looking  vigorous  man  for  his  age.  On  July 
9th,  while  engaged  in  berry  picking  in  a  field  in  Anne  Arundel  Co., 
Md.,  he  suffered  from  heat  stroke,  remaining  unconscious  for  two  hours 
and  having  to  be  carried  to  his  home.  The  next  day  he  was  up  and 
about  again,  and  felt  able  to  work,  but  had  not  been  altogether  well 
since,  having  suffered  from  headaches  and  occasional  chilly  sensations. 

On  admission  the  following  note  was  made :  "  Healthy  looking, 
much  sunburnt,  pulse  full,  walls  of  blood  vessels  soft,  no  oedema  of 
feet.     The  lungs  are  clear  in  front  and  behind ;  the  expiration  is  a 


A  Study  of  Some  Fatal  Cases  of  Malaria.  7 

little  prolonged.  The  apex  beat  of  the  heart  is  neither  visible  nor 
palpable,  the  sounds  are  weak,  the  second  being  scarcely  audible  at 
the  base.  The  area  of  liver  dullness  is  reduced.  The  spleen  is  not 
enlarged ;  the  urine  is  light  yellow  in  color,  specific  gravity,  1010 ; 
no  albumen,  no  casts." 

Concerning  the  further  progress  of  the  case,  we  have  the  following 
account  from  Prof.  Osier. 

"  I  saw  the  patient  only  during  the  first  four  days  of  his  stay  at  the 
Hospital,  and  thought  that  he  was  suffering  from  the  effects  of  a  sun- 
stroke. He  was  given  a  tonic  mixture.  The  patient's  temperature 
was  normal,  but  on  the  20th  and  21st  the  morning  records  were  97.6° 
and  97.8°  respectively. 

On  the  25th,  at  11.30,  he  had  a  chill;  the  temperature  rose  to 
105°  and  remained  high  all  the  afternoon.  At  7.30  p.  m.  it  was 
again  105°,  and  he  was  given  a  graduated  bath. 

Throughout  the  26th  the  temperature  fell,  but  did  not  go  below 
101°  ;  the  pulse  was  rapid  and  feeble. 

On  the  27th  the  temperature  at  8  a.  m.  was  100.5° ;  in  the  after- 
noon it  rose  to  103°,  and  in  the  evening  was  100.3°  ;  pulse,  104, 
extremely  irregular  and  intermittent.  There  were  feeble  r^les,  with 
a  high  pitched  percussion  note  in  the  right  infra-scapular  region. 
Towards  evening  the  patient  sweated  profusely  and  the  breathing  was 
of  the  Cheyne-Stokes  type. 

On  the  28th  the  temperature  fell  rapidly,  sinking  from  103°  at  4 
p.  m.  of  the  27th  to  97.3°  at  8  a.  m.  of  the  28th,  and  to  95.5°  at  10 
a.  m.  The  pulse  was  extremely  feeble  and  irregular.  He  vomited 
twice.  There  has  been  no  expectoration.  The  breath  sounds  at  the 
right  base  have  been  very  feeble.  Throughout  the  afternoon  of  the 
28th  the  temperature  rose  and  at  8  p.  m.  was  100°. 

On  the  29th  the  Cheyne-Stokes  breathing  persisted,  and  the  patient 
had  slight  diarrhoea.  His  speech  was  disturbed  but  he  appeared  to 
be  conscious.  Throughout  the  30th,  31st  and  August  1st  he  sank 
gradually  and  died  on  the  morning  of  the  2d. 

I  did  not  see  the  patient  from  the  date  of  his  chill  until  the  morning 
of  the  2d,  just  before  his  death.  The  case  was  regarded  as  one  of  low 
anomalous  pneumonia.  The  day  after  the  chill  it  is  stated  in  the  note 
that  the  blood  was  examined  with  negative  results ;  but  there  is  no 
initial  to  indicate  by  whom  the  examination  was  made." 


8  Lewellys  F.  Barker, 

Autojjsy. — (Professor  Welsh.)  (Abstract  from  the  records  of  the 
Pathological  Laboratory). 

Anatomical  Diagnosis. — Malarial  fever,  with  malarial  parasites  in 
the  blood  and  spleen;  soft,  swollen,  pigmented  spleen;  pigmented 
and  myristicated  liver ;  pulmonary  emphysema  ;  general  muco-puru- 
lent  bronchitis ;  pulmonary  oedema ;  catarrhal  colitis. 

Exterior. — Body,  168  cm.  long  ;  much  emaciated.  Hernial  tumor 
in  each  groin.  Rigor  mortis  well  marked.  Livor  mortis  in  dependent 
parts.  On  belly  and  chest  are  a  number  (20-30)  dark  red  liver  spots, 
slightly  elevated,  which  do  not  disappear  on  pressure. 

Abdominal  Cavity. — Loops  of  small  intestine  lie  loosely  in  the  her- 
nial sacs  which  open  by  wide  mouths  at  internal  inguinal  rings  into 
the  peritoneal  cavity.  Spots  of  fibrous  thickening  on  peritoneum 
covering  mesentery  of  small  intestine.  Old  pigmented  patches  on 
pelvic  peritoneum.  Firm  old  adhesions  binding  tightly  together  the 
under  surface  of  the  liver  and  gall-bladder  with  the  adjacent  parts  of 
the  duodenum  and  ascending  and  transverse  colon.  The  capsule  of 
the  liver  along  its  anterior  border  and  on  the  adjacent  convexity  is 
opaque,  white,  thickened  and  wrinkled,  owing  to  old  fibrous  thick- 
ening. The  diaphragm  on  the  right  side  reaches  the  lower  margin 
of  fifth  rib,  on  left,  lower  margin  of  sixth  rib.  The  peritoneal  cavity 
contains  about  50  cc.  of  clear  yellowish  serum. 

Thoracic  Cavity. — The  anterior  surface  of  the  pericardium,  save  a 
triangular  area  much  smaller  than  normal,  is  covered  with  the  em- 
physematous lungs.  There  are  old  fibrous  adhesions  between  the 
pleural  surfaces  of  the  posterior  parts  and  apices  of  both  lungs.  On 
anterior  surface  of  middle  lobe  of  right  lung  are  some  old  white 
fibrous  nodules,  the  size  of  a  pin's  head  and  larger.  There  is  a  small 
amount  of  clear  serum  in  each  pleural  cavity  and  also  in  the  peri- 
cardial cavity. 

Heart. — Weight,  290  grams ;  small ;  myocardium  of  a  deep  brown 
color ;  some  thickening  of  aortic  and  mitral  valves  along  lines  of 
closure,  but  apparently  not  enough  to  interfere  with  the  functions  of 
the  valves.  Some  atheromatous  deposits  in  pockets  of  aortic  valves. 
Endocardium  of  left  ventricle  thickened  and  opaque.  No  fibrous 
patches  in  myocardium  except  at  tips  of  musculi  papillares.  Chordae 
tendineae  of  mitral  valve  somewhat  thickened  and  retracted.  The 
coronary  arteries  present  near  their  origin  moderate  atheromatous 


A  Study  of  Some  Fatal  Cases  of  Malaria.  9 

thickening,  and  are  rather  tortuous.  Loose  dark  red  clots  and  some 
decolorized  post-mortem  clots  in  both  ventricles. 

Lungs. — Markedly  emphysematous,  swollen,  not  collapsing  readily, 
of  a  soft  cushiony  feel,  air  cells  in  anterior  part  of  lungs  near  inner 
margin  reach  size  nearly  of  pins'  heads.  Considerable  pigmentation 
with  coal.  On  section  the  dependent  parts  of  lung  are  much  con- 
gested and  there  is  moderate  general  oedema.  Both  large  and  smaller 
bronchi  contain  much  muco-pus,  which  can  be  squeezed  out  in  opaque 
thick  whitish  drops.  The  bronchitis  is  general.  The  pulmonary 
parenchyma  everywhere  contains  air.  There  is  no  pneumonia.  On 
pleura  at  apices  of  both  lungs  are  some  old  fibrous  scars  and  immedi- 
ately beneath  the  pleura  are  a  few  old  black  calcified  nodules  the  size 
of  split  peas. 

Spleen. — Weight,  192  grams ;  length,  13  cm. ;  width,  8  cm. ;  thick- 
ness, 3.5  cm.  The  capsule  is  extensively  thickened  and  opaque,  and 
the  organ  is  surrounded  by  old  fibrous  adhesions.  The  consistence  is 
soft,  the  organ  being  almost  diffluent  on  section.  Color,  dark  browQ 
or  blackish-brown.  Malpighian  bodies  not  readily  distinguishable 
in  the  soft  dark -colored  pulp. 

Kidneys. — Surface  smooth,  save  some  indication  of  foetal  lobulation. 
Capsules  not  adherent.  Cortex  measures  6  mm.  in  thickness ;  striae 
distinct  and  regular.  Weight  of  each  kidney  196  grams.  Dimensions, 
10  X  5  cm.  There  is  a  small  white  fibroma  the  size  of  a  split  pea  in 
cortex  of  left  kidney.     Adrenals  apparently  normal. 

Bladder. — Contains  about  5  cc.  of  whitish  fluid.  Mucosa  normal. 
Prostate  moderately  enlarged  and  contains  many  corpora  amylacea. 

lAver. — Weight,  1650  grams.  Dimensions,  24  x  15  x  6.5  cm.  Cap- 
sule opaque  and  thickened  along  anterior  margin.  Prevailing  color 
on  section  brown  or  bronzed.  Centers  of  acini  of  a  reddish  brown, 
peripheries  of  a  lighter  brownish  color.  The  gall  bladder  contains  a 
moderate  amount  of  brownish  yellow  bile ;  bile  duct  patent. 

Pancreas. — Firm,  pale,  normal. 

Large  Intestine. — Rectum  contains  very  hard,  yellowish  scybala 
coated  with  mucus.  Balls  of  firm  yellow  faeces  in  colon  and  caecum. 
Mucous  membrane  of  large  intestine,  particularly  of  sigmoid  flexure 
and  colon,  coated  with  firmly  adherent,  stringy,  very  tenacious,  white 
mucus,  often  peculiarly  arranged  in  irregular  anastomosing  lines. 
The  mucus  is  about  of  the  consistence  observed  in  the  discharges  of 
mucous  or  membranous  diarrhoea. 


10  Lewdlys  F.  Barker. 

Small  Intestine. — Contains  fluid  or  semi-fluid  yellow  material  and 
presents  areas  of  hyperaemia  and  of  coating  with  mucus. 

Stomach. — Contains  a  little  partially  digested  food.  Mucous  mem- 
brane of  pyloric  region  coated  with  a  thin  layer  of  mucus.  On 
anterior  wall,  4  cm,  from  pylorus,  is  a  mucous  polypus  6  mm.  long,  and 
4  mm.  thick,  with  a  smooth,  round  extremity ;  not  constricted  at  base. 
Near  base  of  polypus  is  a  round  depression  with  smooth  edges  and 
floor  communicating  with  an  oblong  depression  by  a  narrow  similar 
but  elongated  depression.  The  round  depression  is  3  mm.  in  diameter, 
the  oblong  measures  4  x  2  mm.  These  depressions  extend  in  depth 
to  about  that  of  the  mucous  membrane.  The  floor  of  the  depressions 
looks  as  if  covered  with  smooth  mucous  membrane.  There  is  no 
stellate  cicatricial  tissue  in  or  near  these  depressions,  nor  is  there  any 
evidence  of  change  on  the  outer  surface  of  the  stomach. 

Brain. — Arteries  of  base  very  atheromatous  ;  considerable  increase 
of  cerebro-spinal  fluid;  white  substance  of  hemispheres  presents 
numerous  puncta  vasculosa.     Brain  otherwise  appears  normal. 

Microscopical  examination  of  blood  from  finger  shows  a  few  pale 
bodies  of  shape  and  size  of  red  corpuscles  or  larger,  containing  pig- 
mented Plasmodia ;  also  free  round  pigmented  corpuscles,  the  pigment 
in  molecular  movement  (varying  in  size  from  blood  plate  to  twice  this 
size) ;  also  pigmented  crescents,  the  pigment  in  a  ring  in  the  middle ; 
in  one  specimen  of  splenic  pulp  two  actively  moving  free  flagella. 
In  the  capillaries  of  the  brain  are  a  few  pigmented  corpuscles. 

Examination  of  the  hardened  tissues. — A  microscopical  study  of  the 
organisms  and  tissues  confirms  the  findings  at  autopSy  and  the  di- 
agnosis of  an  aestivo-autumnal  malarial  infection.  The  unequal  dis- 
tribution of  the  parasites  and  especially  the  accumulation  of  immense 
numbers  of  them  in  the  capillaries  of  the  mucous  membrane  of  the 
stomach  render  this  case  of  more  than  ordinary  interest. 

The  Liver. — On  examination  with  very  low  powers  (8  to  16  di- 
ameters) there  are  very  few  pigment  masses  large  enough  to  attract 
notice;  in  marked  contrast  to  what  could  be  observed  with  these 
powers  in  the  liver  of  Case  C  (tertian  infection). 

With  higher  powers  intravascular  phagocytes,  especially  macro- 
phages, are  seen  to  be  comparatively  few  in  number.  The  malarial 
parasites  are  not  especially  numerous  in  the  liver.  They  vary  in  size, 
and  have  a  yellow  tint  in  tissues  hardened  in  Miiller's  fluid ;  some 


A  Study  of  Some  Fatal  Cases  of  Malaria.  11 

contain  almost  no  pigment ;  others  contain  very  fine  granules  of 
brownish  black  pigment ;  still  others  contain  distinct  dark  central 
blocks  of  pigment.  A  few  of  the  organisms  appear  to  be  free  in  the 
blood  or  included  within  red  corpuscles.  The  majority  are  inside  mono- 
nuclear leucocytes ;  a  few  have  been  taken  up  by  polynuclear  leucocytes. 
The  latter  cells  also  contain  free  pigment  in  granules  and  blocks. 
There  is  marked  participation  of  the  endothelial  cells  of  the  capillaries 
of  the  liver  in  the  phagocytic  process.  These  cells,  the  cells  of  Kupifer 
and  the  iutracapillary  macrophages  contain  a  few  parasites,  pigment 
in  granules  and  in  blocks,  infected  and  non-infected  red  corpuscles, 
fragments  of  corpuscles,  and  particles  of  irregular  size  and  shape  that 
yield  the  blue  iron-reaction.  Some  of  the  phagocytic  cells,  especially 
the  endothelial  cells,  contain  brassy  corpuscles  (globuli  rossi  ottonati 
of  the  Italians).  From  many  of  the  pigmented  capsules  in  the  larger 
cells  fine  lines  of  yellowish  brown  pigment  can  be  seen  radiating  out 
into  the  protoplasm.  The  pigment  is  chiefly  situated  in  cells  at  the 
periphery  of  the  lobules.  In  certain  areas  bright  yellowish  pigment 
in  considerable  quantities  can  be  seen  running  along  the  rows  of  liver 
cells.  The  liver  cells  themselves  are  large,  swollen,  finely  granular 
and  often  vacuolated.  The  nuclei  of  the  liver  cells  vary  in  size  and 
in  vesicularity.  The  central  veins  of  the  lobules  and  the  neighboring 
capillaries  are  dilated  and  the  liver  cells  near  them  contain  brownish 
pigment.  The  spaces  between  the  liver  cells  and  the  capillary  walls 
are  exaggerated.  Some  of  the  liver  cells  themselves  contain  malarial 
pigment.  No  areas  of  necrosis  can  be  made  out,  but  as  no  tissues 
from  this  case  were  preserved  in  absolute  alcohol  small  necroses  could 
easily  be  overlooked.  There  is  a  slight  excess  of  lymphoid  cells  in 
the  portal  spaces,  and  a  few  larger  pigmented  cells  are  present  in  the 
connective  tissue  of  these  spaces. 

The  Spleen. — The  blood  vessels  are  distended,  especially  those  of  the 
pulp.  In  places  there  are  actual  haemorrhages  into  the  pulp  tissue, 
and  numerous  red  corpuscles  can  be  made  out  among  the  cells  of  the 
pulp-cords.  The  capsule  of  the  spleen  is  slightly  thickened  and  the 
stroma  is  denser  than  normal.  There  is  an  astonishingly  large  number 
of  organisms  present.  These  vary  in  size,  and  are  of  the  aestivo- 
autumnal  variety,  the  majority  appearing  to  be  nearly  full  grown. 
They  are  not  numerous  in  the  larger  vessels  of  the  spleen,  but  are 
very  abundant  in  the  blood  of  the  smaller  vessels  of  the  splenic  pulp. 


12  Lewellys  F.  Barker . 

A  large  number  of  well  formed  organisms,  infected  corpuscles,  remains 
of  organisms  and  corpuscles,  and  fine  and  coarse  pigment  are  con- 
tained within  phagocytes.  The  macrophages  are  of  about  the  same 
size  or  a  little  larger  than  those  described  in  the  liver.  Many  of 
them  contain  brassy  corpuscles.  The  endothelial  cells  and  the  cells 
of  the  splenic  pulp  itself,  as  well  as  the  mononuclear  leucocytes,  con- 
tain foreign  products.  Here  and  there  a  large  vesicular  parasite  with 
very  little  pigment  is  visible,  and  a  few  crescents  can  be  made  out, 
although  they  are  probably  much  more  numerous  than  the  study  of 
hardened  tissues  alone  might  have  led  us  to  infer.  They  were  present 
in  considerable  numbers  in  the  fresh  blood  taken  from  the  spleen  at 
autopsy,  but  on  account  of  the  deformity  resulting  from  hardening 
and  the  pallor  of  the  bodies  of  these  forms,  we  have  experienced  the 
same  difficulty  in  recognizing  them  in  sections  which  has  attended  the 
studies  of  other  observers.  The  pigment  is  mainly  contained  in  the 
splenic  pulp ;  the  Malpighian  bodies  are  comparatively  free  from  it, 
and  when  pigment  is  to  be  made  out  in  the  latter,  it  is  usually  included 
within  large  cells  around  the  arterioles. 

The  Kidney. — There  is  a  moderate  degree  of  chronic  diffuse  ne- 
phritis, some  of  Bowman's  capsules  showing  slight  fibrous  thickening. 
The  glomeruli  for  the  most  part  fill  the  capsular  spaces.  A  moderate 
amount  of  pigment  is  to  be  seen  within  the  glomeruli,  chiefly  con- 
tained in  the  endothelium  of  the  glomerular  capillaries ;  some  of  it 
being  within  mononuclear  cells  inside  the  capillaries.  The  endothelial 
cells  of  the  intertubular  capillaries  and  of  the  small  veins  contain 
occasionally  at  the  poles  of  their  nuclei  granules  and  masses  of 
malarial  pigment.  Occasionally  inside  the  vessels  a  mononuclear  cell 
containing  one  or  more  tolerably  well  preserved  organisms  can  be  made 
out.  No  parasites  were  seen  in  the  kidney  outside  of  phagocytes. 
The  epithelium  lining  the  convoluted  tubules  is  swollen  and  filled 
with  fine  granules.  Some  of  the  cells  are  actually  necrotic,  the  nuclei 
refusins:  to  stain.  A  number  of  the  tubules  in  the  cortex  contain 
within  the  protoplasm  of  their  lining  epithelium  masses  of  bright 
yellow  pigment.  Occasionally  hyaline  casts  are  met  with  in  the 
collecting  tubules. 

The  Stomach. — The  findings  in  the  sections  of  the  stomach  are  of 
interest.  The  capillaries  and  veins  of  the  mucous  membrane  are 
widely  dilated,  many  of  the  larger  and  smaller  veins  being  engorged 
with  red  blood  corpuscles,  whose  outlines  are  perfectly  well  preserved. 


A  Study  of  Some  Fatal  Cases  of  Malaria.  13 

and  in  certain  areas  inside  nearly  every  red  corpuscle  is  a  parasite 
with  a  central  block  of  brownish  black  pigment.  Along  with  these 
masses  of  infected  corpuscles  there  are  often  found  numerous  mononu- 
clear macrophages  crowded  with  blocks  of  malarial  pigment  like  that 
to  be  seen  in  the  infected  corpuscles.  There  are  places  where  the 
lumina  of  the  veins  appear  to  be  narrowed  near  the  base  of  the  mucous 
membrane  and  as  though  blocked  with  macrophages  damming  back 
infected  corpuscles.  The  arteries  and  veins  of  the  submucosa  are 
singularly  free  from  infected  corpuscles.  The  distribution  of  the 
parasites  in  the  capillaries  is  very  irregular ;  while  in  one  area  all  of 
the  capillaries  may  be  closely  crowded  and  distended  with  infected 
corpuscles,  in  other  places  quite  near  by  the  vessels  may  be  almost 
entirely  free  from  them.  Besides  the  macrophages  already  described 
there  are  large  red-corpuscle-carrying  cells  within  the  veins  and  ca- 
pillaries, filled  with  blood  corpuscles  which  stain  intensely  with  eosin. 
These  cells  contain  large  single  nuclei  which  often  send  out  processes 
among  the  red  corpuscles  in  the  protoplasm.  Some  of  the  smaller 
vessels  appear  to  have  their  lumina  entirely  filled  with  huge  cells  of  the 
kind  describedj  forming  veritable  casts.  These  cells  must  exercise 
considerable  influence  in  obstructing  the  on-flow  of  blood.  The  surface 
of  the  mucous  membrane  in  maoy  places  refuses  to  stain,  and  frag- 
mented nuclei  are  visible  evidences  of  superficial  necrosis. 

The  Heart. — There  is  an  excess  of  brown  pigment  at  the  poles  of  the 
nuclei  of  the  muscle  cells ;  otherwise  there  are  no  striking  alterations. 

Cerebrum. — Only  an  occasional  infected  corpuscle  can  be  made  out 
within  the  capillaries ;  a  few  of  the  endothelial  cells  lining  the  capil- 
laries are  phagocytic.  Portions  were  saved  from  only  one  or  two 
parts  of  the  cortex. 

Thyroid  Gland. — In  the  vessels  of  this  organ  as  elsewhere  in  the 
peripheral  circulation  it  is  rarely  that  infected  red  blood  corpuscles 
are  to  be  seen. 

III. 

Case  B. — Aestivo-autumnal  malaria  ;  grave  abdominal  symptoms. 

John  B.,  age  34,  admitted  to  the  Johns  Hopkins  Hospital,  Sep- 
tember 10th,  died  September  16th,  1890.  The  following  is  Prof. 
Osier's  clinical  note  of  the  case  : 


14  Lewellys  F.  Barker. 

"I  saw  him  in  the  dispensary  at  1.30  p.  m.  He  was  very  weak 
and  tremulous,  with  eyes  congested,  cheeks  flushed,  and  with  a  dazed, 
stupid  appearance.  The  tongue  was  swollen,  heavily  furred  and  in- 
dented. He  looked  like  a  man  who  had  been  drinking,  and  I  told 
his  brother  that  it  would  be  impossible  for  us  to  admit  him  to  the 
wards  in  his  present  state.  He  assured  me,  however,  that  he  had  not 
been  drinking  to  excess,  and  on  ascertaining  that  there  was  not  the 
slightest  trace  of  salcoholic  odor  in  the  breath,  I  signed  the  order  for 
his  admission. 

The  following  history  was  obtained.  Family  and  personal  history 
good.  The  patient  is  a  sailor  by  occupation,  and  has  enjoyed  excellent 
health  ;  he  left  Boston  for  Savannah  five  weeks  ago  ;  spent  a  week  in 
the  latter  place,  and  as  the  weather  was  oppressive  he,  with  several 
of  his  shipmates,  was  in  the  habit  of  sleeping  on  the  grass  all  night. 
He  remained  well  on  the  voyage  to  Baltimore,  where  he  landed  August 
31st.  He  was  about  the  house  all  the  week,  though  not  feeling  quite 
himself,  but  the  present  illness  dates  from  Sunday  the  7th,  when, 
without  any  chill  or  fever,  he  began  to  have  vomiting.  He  felt  ex- 
tremely weak  and  prostrated,  so  that  he  could  not  get  up  on  Monday 
morning.  Throughout  Monday  and  Tuesday  the  vomiting  continued 
at  intervals  and  he  was  completely  prostrated.  He  had  no  chills,  but 
on  Monday  and  Tuesday  he  took  some  quinine  pills.  In  the  dis- 
pensary, after  failing  to  detect  any  alcoholic  odor  in  his  breath,  and 
on  learning  that  he  had  recently  come  from  the  South,  the  blood  was 
at  once  examined  ;  large  numbers  of  Laveran's  organisms  were  found, 
which  rendered  the  diagnosis  clear.  His  temperature  on  admission 
into  the  ward  was  101°,  pulse  104,  small,  tension  not  increased,  ra- 
dials  not  stiff.  The  abdomen  was  soft ;  nowhere  tender.  The  edge 
of  the  spleen  was  just  palpable  on  deep  inspiration ;  upper  border  of 
dullness  at  the  ninth  rib. 

Apex  beat  of  heart  in  5th  interspace  within  nipple  line ;  sounds 
clear ;  examination  of  the  lungs  negative. 

Blood. — Small  intra-corpuscular  forms  in  extraordinary  abundance, 
often  6  or  8  to  be  seen  in  the  field  of  the  tV  im.  The  majority  of  them 
are  not  pigmented  and  undergo  very  rapid  changes  in  outline.  The 
pigmented  forms  have  the  granules  more  concentrated  than  is  usual 
in  this  stage  of  the  evolution  of  the  parasites.  An  unusual  number 
of  the  leucocytes  present  pigment  granules.  » 


A  Study  of  Some  Fatal  Cases  of  Malaria.  15 

11th.  Very  bad  night ;  much  vomiting  ;  temperature  sank  to 
98.6°  at  10  p.  m.,  and  to  98.2°  by  8  a.  m.  At  the  morning  visit  the 
patient  looked  depressed;  tongue  heavily  furred ;  pulse  80,  small  and 
thready ;  respirations  20.  Had  no  headache  and  complained  chiefly 
of  profound  weakness.  At  noon  the  temperature  began  to  rise  and 
at  4  p.  m.  reached  102.2°,  and  for  6  or  8  hours  remained  about 
102°,  gradually  falling  through  the  early  morning  hours  and  at  8 
a.  m.  reaching  98.5°.  The  blood  condition  remains  practically  about 
the  same. 

12th.  10  a.  m.  Patient  passed  a  better  night.  The  vomiting  has 
stopped  but  the  tongue  is  still  furred  ;  no  increase  in  the  splenic  dull- 
ness. The  bowels  have  been  freely  opened.  He  still  looks  depressed 
and  dull,  and  complains  of  a  feeling  of  great  prostration. 

13th.  Temperature  has  been  about  98°  for  the  past  24  hours, 
pulse  72,  small.  The  vomiting  has  not  been  so  distressing,  and  he 
has  taken  the  milk  and  brandy  better  than  on  any  day  since  admission. 
The  blood  examination  shows  a  marked  diminution  in  the  number  of 
corpuscles  containing  the  plasmodia,  the  diminution  being  doubtless 
due  to  the  influence  of  the  quinine. 

14th.  Temperature  has  been  subnormal,  not  rising  above  97.5°  all 
day.  The  vomiting  has  returned,  and  for  the  first  time  the  vomitus 
contained  blood,  not  in  large  amount,  but  sufficient  to  color  the  fluid. 
His  mind  is  perfectly  clear,  and  his  sole  complaint  is  of  the  extreme 
depression. 

15th.  10  a.  m.  Patient's  condition  is  worse  since  8  p.  m.  last 
evening.  The  temperature  has  been  below  97°,  and  at  12  midnight 
sank  to  96°  ;  pulse,  64  ;  respirations,  20.  Tongue  still  swollen,  heavily 
furred  and  indented.  Note  on  the  blood  to-day  is  :  "  plasmodia  very 
much  diminished  in  number.  Leucocytes  still  show  much  pigmen- 
tation." The  urine  is  amber  colored,  specific  gravity,  1010 ;  acid, 
contains  a  slight  amount  of  albumen.  At  9  p.  m.  I  made  the  fol- 
lowing note:  "Patient  is  in  a  very  peculiar  condition;  is  drowsy, 
dull,  roused  with  difficulty,  and  does  not  answer  clearly.  He  has 
behaved  oddly  all  day,  and  has  been  very  restless.  There  has  been 
very  little  vomiting ;  temperature  has  been  subnormal,  and  is  now 
96.5°.     For  the  first  time  the  tongue  is  distinctly  dry," 

16th.  Through  the  night  the  patient  was  very  restless  and  had 
much  hiccough  ;  was  not  delirious,  but  acted  queerly.     The  tempera- 


16  Lewellys  F.  Barker. 

ture  sank  through  the  night,  and  at  2  a.  m.  was  96°  ;  at  4  a.  m.  the 
thermometer  could  not  be  made  to  register  more  than  95°,  and  the 
temperature  remained  at  this  point  until  10  a.  m.  The  vomited  matter 
last  night  contained  flakes  of  blood  enough  to  tinge  the  whole  fluid. 
He  had  retention  of  urine  and  this  morning  1500  cc.  were  withdrawn, 
which  showed  a  narrow  ring  of  albumen  and  contained  hyaline  and 
granular  tube-casts.  The  nurse  says  that  he  does  not  understand 
questions,  but  he  seemed  to  recognize  me,  and  gave  fairly  rational 
answers,  but  complained  of  great  oppression  in  the  abdomen.  The 
pulse  is  72,  and  considering  his  condition  the  volume  and  tension  were 
remarkably  good.  At  6  p.  m.  I  made  the  following  note  :  "  Tempera- 
ture has  risen  through  the  day  and  is  now  97.2°.  The  tongue  is  dry, 
pulse  96,  regular  and  of  very  fair  volume.  He  is  extremely  restless, 
and  his  face  has  a  dusky  hue ;  the  respirations  are  at  times  gasping, 
24  to  the  minute.  He  answers  questions,  but  talks  and  rambles  in 
an  incoherent  way.  To-day  very  few  red  blood  corpuscles  have  been 
found  containing  plasmodia ;  the  leucocytes  are  still  much  pigmented." 
Patient  became  much  more  restless,  threw  himself  about  on  the  bed, 
then  became  unconscious,  and  died  at  8  o'clock.  The  treatment  con- 
sisted of  half-drachm  doses  of  quinine  every  six  hours,  which  was 
given  hypodermically  when  the  vomiting  became  excessive. 

Autopsy  15  hom^s  after  death. — Body  161  cm.  long,  well  nourished, 
post-mortem  discoloration  of  dependent  parts  and  of  face  and  neck. 
Peritoneum  smooth,  a  little  darkened  and  slaty  in  appearance,  no  ex- 
cess of  fluid  in  abdominal  cavity.  No  pleural  adhesions  ;  pericardial 
and  pleural  cavities  dry.  Right  side  of  heart  distended  with  fluid 
blood  ;  left  ventricle  empty  and  contracted.  Heart  valves  all  normal 
except  for  slight  atheroma  at  attached  borders  of  aortic  cusps.  Myo- 
cardium pale,  otherwise  normal ;  left  lung  crepitant,  anteriorly  and 
in  lower  part  of  upper  lobe  congested  and  ©edematous.  Right  lung 
still  more  ©edematous,  deeply  engorged  at  base.  A  small  piece  cut 
from  extreme  posterior  part  of  lower  lobe  on  this  side  sinks  in  water. 
The  bronchi  contain  frothy  mucus. 

The  Spleen  and  Liver. — The  spleen  measures  8  x  13  cm.,  is  ex- 
tremely soft,  almost  diffluent.  The  pulp  is  of  a  dirty  brownish-red 
hue ;  the  capsule  is  thin  and  shows  a  few  superficial  hemorrhages. 
The  liver  is  large,  slate-gray  in  color ;  its  capsule  is  slightly  thick- 


A  Study  of  Some  Fatal  Cases  of  Malaria.  17 

ened  and  opaque.  Just  above  the  gall  bladder  on  section  the 
substance  is  moderately  firm  and  has  a  uniform  bronze  or  slaty  tinge. 
The  outlines  of  the  lobules  are  not  well  defined.  There  is  deep 
pigmentation  about  the  portal  canals  and  the  smaller  bile  ducts  are 
distended. 

The  Kidneys  are  large  and  swollen  ;  the  surfaces  are  mottled. 
The  capsules  are  adherent  in  places.  On  section  the  consistence  is 
firm.  The  Malpighian  tufts  are  prominent  and  congested ;  the 
medullary  rays  are  pale  and  between  them  the  lines  of  vessels  are 
deeply  reddened.  No  areas  of  opacity  are  visible.  The  cortex  is 
distinctly  though  slightly  pallid.  The  adrenals  show  no  marked 
alteration. 

The  Stomach. — Contents  are  liquid  and  of  a  yellowish  color.  The 
mucous  membrane  has  a  slatish-grey  tint,  and  on  the  anterior  surface 
near  the  lesser  curvature  are  the  scars  of  two  small  ulcers  and  on  the 
posterior  wall  three  other  flat  cicatrices  are  visible.  The  bile  duct  is 
patent  and  the  portal  vein  is  free.  The  contents  of  the  small  intestine 
are  reddish-brown  in  color,  the  mucous  membrane  is  congested  in 
places.  Peyer's  patches  are  not  swollen,  although  the  lower  ones 
have  a  shaven  beard  appearance.  The  colon  is  deeply  congested  in 
places  and  covered  with  tenacious  yellow  faeces.  There  is  no  in- 
testinal ulceration. 

The  Brain. — The  dura  presents  on  its  surface  well  back  on  the 
right  side  a  small  hemorrhage.  The  pia  over  the  cortex  is  smooth, 
in  it,  over  the  middle  of  the  first  right  frontal  convolution  close  to 
the  longitudinal  sinus,  is  an  area  of  brownish-black  pigmentation 
about  1  cm.  in  diameter.  The  membranes  and  vessels  at  the  base 
appear  normal.  On  section  the  substance  of  the  brain  looks  natural 
except  for  turgidity  of  the  vessels. 

Microscopical  Examination. —  The  Liver. — The  malarial  pigment  is 
situated  chiefly  in  the  outer  half  of  the  lobules  and  is  principally  en- 
closed in  cells.  The  liver  capillaries  are  engorged  with  blood.  In 
some  of  these  many  of  the  red  corpuscles  contain  malarial  parasites 
which  vary  in  size  from  extremely  minute  forms  to  larger  bleb-like 
organisms  almost  as  large  as  the  corpuscles.  Some  of  these  parasites 
contain  only  a  little  fine  pigment ;  others  none  at  all.  Some  of  the 
liver  capillaries  are  quite  free  from  parasites,  while  others  are  crowded 
with  organisms  each  containing  a  central  block  of  brownish-black 


18  Lewellys  F.  Barker. 

pigment.  A  few  of  the  intra-corpuscular  organisms  not  enclosed  in 
phagocytes  show  fine  lines  of  yellowish  pigment  granules  radiating 
from  them,  which  appear  sometimes  to  extend  beyond  the  limits  of 
the  corpuscle  in  which  they  are  contained.  Most  of  the  organisms 
are  contained  within  cells.  In  this  case  the  endothelium  of  the  hepatic 
capillaries  and  the  cells  of  Kupffer  have  played  the  greatest  role  in 
the  phagocytosis.  There  are  some  large  mononuclear  intra-vascular 
phagocytes,  but  most  of  the  organisms  and  the  remnants  of  organisms 
are  contained  within  the  protoplasm  of  the  endothelial  cells,  being 
often,  though  not  always,  situated  at  the  poles  of  the  nuclei.  In  the 
intra-capillary  macrophages,  which  are  of  smaller  size  than  those 
occurring  in  the  liver  of  Case  D,  the  nucleus  is  frequently  surrounded 
by  black  pigment  blocks.  The  swelling  of  the  endothelial  cells  of  the 
capillaries  is  marked,  being  sufficient,  one  would  think,  to  oifer  serious 
impediment  to  the  progress  of  the  blood.  The  liver  cells  themselves 
are  swollen  and  granular,  and  many  of  them  are  filled  with  yellow 
pigment  masses.  In  places  they  are  atrophied  and  the  capillaries  in 
the  atrophied  areas  are  correspondingly  dilated. 

The  Kidneys. — AH  the  blood  vessels  of  these  organs  are  dilated, 
the  veins  of  the  pyramids  being  especially  wide.  There  is  irregular 
dilatation  of  the  glomerular  capillaries.  Comparatively  few  parasites 
are  present  in  the  kidneys,  although  some  distinct  forms  are  visible 
within  the  veins  and  capillaries.  A  small  number  of  phagocytic  cells 
can  be  seen  (intra-vascular  phagocytes  and  endothelial  cells).  The 
capsules  of  some  of  the  glomeruli  have  undergone  fibrous  thickening ; 
in  places  the  capsular  endothelium  is  proliferated.  The  epithelium 
of  the  convoluted  tubules  is  swollen  and  granular,  and  there  are 
numerous  hyaline  casts  to  be  seen  in  the  small  collecting  tubules. 
In  the  pyramids  haemoglobin  casts  can  be  made  out. 

The  Brain. — A  few  infected  corpuscles  can  be  seen  within  the  blood 
vessels.  Here  and  there  a  phagocytic  endothelial  cell  occurs.  In 
one  spot  there  is  a  very  small  infarct  showing  necrosis  of  the  cerebral 
tissue,  hyperaemia  at  its  margin,  and  an  accumulation  of  mono-  and 
polynuclear  cells.     There  are  no  other  marked  changes. 

No  other  tissues  were  saved  from  this  case.  This  is  unfortunate, 
since  from  the  grave  gastric  symptoms  observed  during  life  an  ex- 
amination of  the  contents  of  the  capillaries  of  the  mucous  membrane 
of  the  stomach  would  have  been  interesting  (vide  Case  A). 


A  Study  of  Some  Fatal  Cases  of  Malaria.  19 

IV. 

Case  C. — Acute  aestivo-autumnal  malaria ;  death  from  accident ; 
acute  necrotic  lesions  in  the  liver  and  spleen.  Remarks  on  the 
relation  of  malaria  to  cirrhotic  processes. 

R.  G.,  aet.  22.  Pole,  single,  laborer,  admitted  to  Prof.  Osier's 
wards  October  5th,  1892.  He  complained  of  chills  and  fever,  and 
on  entrance  was  suffering  from  a  paroxysm,  during  which  his  tempera- 
ture reached  106.8°  F.  He  had  been  working  at  Locust  Point  (a 
part  of  the  city  near  the  harbor  in  which  malarial  infections  frequently 
occur)  when  he  was  taken  ill,  two  weeks  before  his  application  to  the 
Dispensary  for  treatment.  On  admission  his  blood  was  examined  and 
found  to  contain  only  a  few  hyaline  intra-cellular  parasites. 

The  physical  examination  of  the  heart  and  lungs  yielded  no  ab- 
normal signs.  The  respirations  were  hurried,  the  pulse  was  frequent 
and  slightly  dicrotic.  The  lower  edge  of  the  spleen  could  be  easily 
palpated,  reaching  a  point  two  fingers-breadth  below  the  costal  margin. 
The  liver  dulness  was  not  increased.  The  patient  vomited  everything 
taken  into  the  stomach,  including  the  quinine  administered,  so  that 
other  methods  of  exhibiting  it  had  to  be  resorted  to.  On  the  next 
day  the  blood  was  carefully  examined  twice,  but  no  malarial  parasites 
could  be  found.  The  leucocytes  were  not  increased  in  number.  The 
patient  complained  of  severe  abdominal  pain  on  the  following  day ; 
two  slides  of  blood  were  examined  in  the  early  morning  but  no  ma- 
larial parasites  could  be  found.  The  patient  met  with  an  accident, 
associated  with  profuse  hemorrhage,  and  died  in  the  afternoon. 

At  the  autopsy,  which  was  made  by  Dr.  Flexner  while  the  body 
was  still  warm,  the  typical  lesions  of  an  acute  malarial  infection  were 
found.  There  were  numerous  ecchymoses  scattered  over  various 
parts  of  the  skin  and  over  the  serous  membranes.  The  muscles  were 
brownish-red  in  color.  The  lungs  were  moderately  pigmented ;  the 
heart  valves  were  normal.  Heart's  flesh  pale.  Anterior  mediastinal 
glands  softened  and  reddened. 

Liver. — Weight,  2200  grams ;  surface  smooth ;  substance  of  a  dark 
brown  color ;  consistency  soft ;  lobules  invisible. 

Spleen. — Weighed  800  grams ;  measured  23  x  11  x  5  cm. ;  diffluent ; 
deep  dark  red  in  color ;  Malpighian  bodies  visible ;  pulp  abundant. 
2 


20  Lewellys  F.  Barker. 

Pancreas  and  kidneys  normal ;  stomach,  intestines  and  bladder 
normal.  Lymph  glands  in  hilum  of  spleen  and  about  the  pancreas 
swollen,  softened  and  deeply  congested.  Culture  tubes  of  agar-agar 
inoculated  from  various  organs  at  the  autopsy  remained  sterile. 

The  Spleen:  Microscopic  Examination. — The  lesions  in  this  organ 
resemble  much  those  seen  in  certain  acute  bacterial  infections.  The 
organ,  especially  the  pulp,  is  markedly  hyperaemic.  In  places  there 
are  evidences  of  extravasation.  On  examining  the  pulp  with  higher 
powers  the  contents  of  the  capillaries  and  veins  are  seen  to  be  complex. 
Besides  large  numbers  of  ordinary  red  blood  corpuscles  there  are  a 
number  containing  malarial  parasites  of  the  aestivo-autumnal  type. 
The  majority  of  the  latter,  however,  are  enclosed  within  mononuclear 
cells.  Well  preserved  organisms  are  by  no  means  numerous  and  the 
contents  of  the  phagocytes  consist  largely  of  remains  of  malarial 
organisms  and  shrunken  corpuscles  containing  more  or  less  brownish- 
black  pigment.  The  number  of  red  blood-corpuscle-carrying  cells  is 
much  increased  ;  huge  cyst-like  cells,  usually  mononuclear,  the  nucleus 
sometimes  having  radiating  processes  which  run  out  toward  the  peri- 
phery of  the  cells,  are  seen  sometimes  containing  thirty,  forty,  fifty 
or  more  apparently  well  preserved  red  blood  corpuscles  which  stain 
deeply  in  eosin.  The  pulp  cells  themselves  are  large  and  swollen, 
and  frequently  contain  within  their  substance  other  cells,  chiefly  with 
nuclei  of  the  lymphoid  type ;'  sometimes  also  polynuclear  leucocytes, 
and  very  often  a  number,  five,  ten  or  even  more  completely  colorless 
red  blood  corpuscles.  These  cells  contain  in  addition  infected  red 
blood  corpuscles,  free  malarial  parasites,  the  more  or  less  broken  down 
remains  of  parasites  and  free  malarial  pigment  often  arranged  in 
dotted  lines.  Besides  these  large  mononuclear  cells  in  the  vessels 
there  are  very  many  small  and  large  lymphocytes  seen  crowding  the 
lumina  of  the  vessels.  There  are  also  a  few  polynuclear  leucocytes, 
some  ordinary  large  mononuclear  leucocytes,  and  an  occasional  giant 
cell  with  budding  nuclei,  resembling  those  normally  present  in  the 
bone  marrow.  The  protoplasm  of  many  of  the  cells  in  the  pulp-cords 
stains  deeply  in  eosin.  Sometimes  the  protoplasm  of  these  cells  is 
highly  refractive  and  the  nucleus  does  not  stain  at  all,  or  it  may  be 
broken  up  into  a  number  of  fragments  irregular  in  size  and  shape. 
In  these  cells  one  or  more  polynuclear  leucocytes  are  often  to  be  seen, 
the  hyaline  protoplasm  being  sometimes  closely  crowded  with  them. 


A  Study  of  Some  Fatal  Cases  of  Malaria.  21 

In  some  places  in  the  pulp  there  are  actual  focal  necroses,  very- 
much  like  those  which  are  to  be  seen  in  typhoid  fever.  In  these, 
particularly  in  the  more  recent  ones,  large  necrotic  cells  with  hya- 
line protoplasm  and  fragmented  nuclei  can  be  made  out  along  with 
lymphoid  cells,  polynuclear  leucocytes  and  endothelioid  cells.  In 
the  larger  necroses  the  necrotic  cells  may  be  almost  entirely  obscured 
by  the  collection  of  lymphoid  cells  and  the  leucocytes  with  poly- 
morphous nuclei.  In  these  areas  there  is  evidence  of  division  by 
amitosis  with  distortion  of  the  nuclei  (abschniirungsvorgange),  and 
scattered  among  the  cells  a  number  of  minute  nuclear  fragments  are 
visible.  There  are  also  in  these  areas  large  phagocytes  containing 
within  their  protoplasm  malarial  parasites  and  pigment,  polynuclear 
leucocytes,  intact  and  broken  down  red  blood  corpuscles  and  nuclear 
fragments. 

The  endothelial  cells  lining  the  vascular  spaces  are  evidently  pha- 
gocytic. They  contain  within  their  protoplasm,  usually  at  the  poles 
of  the  nuclei,  the  remains  of  malarial  organisms,  broken  down  blood 
cells,  free  malarial  pigment,  and  irregular  masses  of  blood  pigment 
which  yields  the  blue  iron  reaction.  The  Malpighian  corpuscles 
themselves  are  swollen  ;  there  has  been  proliferation  in  the  lymphoid 
cells.  Among  the  lymphoid  cells  can  be  seen  a  few  large  cells  re- 
sembling somewhat  the  cells  of  the  pulp,  often  containing  within 
them  mononuclear  and  polynuclear  cells,  red  blood  corpuscles,  and 
sometimes  malarial  organisms  and  malarial  pigment.  These  are  best 
studied  in  specimens  stained  with  methylene  blue  and  eosin.  Numerous 
capillary  thrombi  can  be  made  out  scattered  through  the  spleen ;  these 
thrombi  resemble  closely  those  seen  in  the  liver  of  this  case.  One 
is  tempted  to  think  of  a  relation  existing  between  these  capillary 
thrombi  and  the  focal  areas  of  necrosis. 

The  Liver.— The  capillaries  generally  are  dilated,  in  some  areas 
more  markedly  than  in  others.  Within  the  capillaries  are  many  red 
blood  corpuscles,  a  few  red  blood-corpuscle-carrying  cells,  lymphoid 
cells,  small  and  large,  a  few  polynuclear  leucocytes,  and  in  some  parts 
of  the  liver  large  phagocytes.  The  latter  may  contain  within  their 
protoplasm,  besides  well  formed  malarial  parasites  of  the  aestivo-au- 
tumnal  type,  shrunken  remains  of  parasites,  fine  malarial  pigment, 
red  corpuscles,  particles  of  haemosiderin,  lymphoid  cells,  and  occa- 
sionally polynuclear  leucocytes.     The  endothelial  cells  lining  the 


22  Lewellys  F.  Barker. 

capillaries  are  in  places  much  swollen,  their  nuclei  are  large  and 
vesicular,  and  within  their  protoplasm  are  sometimes  visible  the  same 
substances  as  those  mentioned  as  occurring  within  the  intra-vascular 
phagocytes.  The  endothelial  cells  are  so  much  swollen  in  places  that 
thej  materially  narrow  the  lumina  of  the  capillaries.  The  spaces 
between  the  capillary  walls  and  the  liver  cells  are  wider  than  normal 
and  there  is  a  considerable  degree  of  atrophy  of  the  rows  of  liver 
cells.  The  liver  cells  contain  an  excess  of  brownish-yellowish  pig- 
ment. Some  of  the  liver  cells  have  giant  nuclei.  The  cells  of  Kupf- 
fer,  between  the  capillary  walls  and  the  rows  of  liver  cells,  are  swollen 
and  some  of  them  are  evidently  phagocytic.  Occasionally  lymphoid 
cells  are  visible  in  the  spaces  between  the  capillary  walls  and  the  liver 
cells.  The  findings  within  the  lumina  of  the  hepatic  capillaries  are 
of  interest.  The  number  of  cells  with  nuclei  of  the  lymphoid  type  is 
astonishing.  Many  of  these  are  of  the  size  of  ordinary  lymphocytes, 
others  being  somewhat  larger.  Occasionally  cells  containing  baso- 
philic granules  within  their  protoplasm  are  visible  within  the  capil- 
laries, and  in  one  or  two  instances  they  are  seen  included  within  the 
protoplasm  of  makrophages.  In  one  section  two  or  three  cells  within 
the  capillaries  possessed  budding  nuclei  quite  like  those  of  the  giant 
cells  in  normal  bone  marrow.  One  of  these  of  large  size  appeared  to 
be  acting  as  a  phagocyte  as  it  contained  within  its  protoplasm  malarial 
pigment  and  a  single  mononuclear  cell.  Some  of  the  phagocytes 
which  are  partially  or  completely  necrotic  are  surrounded  or  invaded 
by  leucocytes  with  polymorphous  nuclei.  A  number  of  the  endo- 
thelial cells  are  also  degenerated  or  necrosed.  Single  and  multiple 
liver-cell-necroses  occur  scattered  throughout  the  section,  forming 
necrotic  areas  of  varying  sizes,  sometimes  as  large  as  those  seen  in 
typhoid  fever.  When  one  or  two  liver  cells  only  are  necrotic  the 
lesions  are  tolerably  distinct.  The  nuclei  of  the  necrotic  cells  are 
fragmented  or  absent  and  those  of  the  neighboring  liver  cells  may  be 
shrunken  and  deeply  stained.  The  protoplasm  of  the  cell  is  hyaline, 
stains  deeply  in  eosin,  and  may  be  invaded  by  polynuclear  leucocytes. 
In  larger  areas  the  pictures  are  more  complex  and  somewhat  diffi- 
cult to  explain.  The  necrotic  liver  cells  have  either  been  removed 
or  are  obscured  by  the  accumulation  of  other  cells.  In  these  foci 
usually,  however,  the  remains  of  liver  cells  and  of  their  nuclei  are 
visible,  especially  in  the  periphery.     Accumulated  here  are  a  number 


A  Study  of  Some  Fatal  Cases  of  Malaria.  23 

of  cells  with  small  sharply  stained  nuclei,  lymphoid  cells,  polynuclear 
leucocytes,  and  spindle-shaped  cells  with  vesicular  nuclei.  In  addition 
there  may  be  large  phagocytic  cells  containing  lymphoid  cells,  poly- 
nuclear leucocytes,  red  blood  corpuscles,  nuclear  fragments,  and  some- 
times malarial  pigment.  It  is  no  easy  matter  to  decide  as  to  the 
origin  of  all  these  different  cells,  although  with  thin  sections  and 
careful  study  the  source  of  most  of  them  can  be  made  out.  It  is  not 
always  possible,  however,  to  say  what  are  endothelial  cells  and  their 
derivatives,  and  what  are  to  be  regarded  as  blood  cells  and  their 
derivatives.  Some  of  the  small  deeply  stained  nuclei  are  probably  to 
be  looked  upon  as  the  offspring  of  leucocytes  which  have  divided  in 
situ  by  amitosis,  as  the  nuclei  of  these  cells  show  various  distortion 
processes  (abschniirungsvorgange).  Sometimes  a  cell  with  hyaline 
protoplasm  and  a  degenerating  nucleus  can  be  seen  surrounded  by  a 
number  of  cells  whose  protoplasm  overlaps  and  seems  actually  to  be 
mingling  with  the  protoplasm  of  the  degenerating  cell,  although  on 
close  focusing  the  boundaries  of  the  various  cells  can  usually  be  made 
out.  The  cells  inside  necrotic  cells  frequently  show  fragmented 
nuclei  and  hyaline  protoplasm.  The  number  of  cells  inside  a  single 
dead  liver  cell  varies.  In  one  the  nuclei  of  ten  foreign  cells,  most  of 
them  polynuclear  leucocytes,  were  included,  and  the  nucleus  of  one  of 
these  latter  was  fragmented. 

There  are  numerous  thrombosed  capillaries  to  be  made  out  in  thin 
sections  (vide  Plate  V,  Fig.  1).  Sometimes  a  single  capillary  appears 
to  be  occluded,  and  a  few  leucocytes  with  distorted  nuclei  are  seen  lying 
in  the  thrombus.  In  other  places  two  or  more  neighboring  capillaries 
are  plugged,  and  in  addition  to  the  white  cells  in  the  thrombus,  leu- 
cocytes, mono-  and  polynuclear,  can  be  seen  aggregated  in  considerable 
numbers  in  the  neighboring  capillaries.  There  may  be  a  diminution 
in  size,  evidences  of  degeneration,  or  a  total  disappearance  of  neigh- 
boring liver  cells.  Plate  V,  Fig.  2  shows  the  condition  better  than  any 
description.  The  occurrence  of  so  many  of  these  thrombosed  capil- 
laries in  the  same  sections  with  the  areas  of  focal  necrosis  is  suggestive, 
and  one  is  very  much  tempted  to  look  upon  the  larger  areas  of  necrosis 
as  advanced  stages  of  a  process  which  began  with  capillary  thrombosis. 

The  triangular  portal  spaces  present  a  very  peculiar  appearance. 
The  connective  tissue  is  crowded  with  cells  containing  nuclei  of  the 
lymphoid  type  so  that  the  tissue  reminds  one  of  the  structure  of  ordi- 


24  Lefwellys  F.  Barker. 

nary  lymphoid  tissue.  In  the  adventitia  of  the  portal  vein  contained 
apparently  in  loose  spaces  are  very  many  lymphoid  cells.  The  portal 
veins  show  in  section  many  mononuclear  and  a  few  polynuclear  leu- 
cocytes, besides  many  makrophages  such  as  have  been  described  in 
the  splenic  veins  and  in  the  liver  capillaries.  There  were  no  lesions 
of  tuberculosis  anywhere  in  the  body,  and  no  bacteria  were  demon- 
strable by  cultural  methods  or  in  sections  of  the  organs. 

The  Kidney. — ^The  lumina  of  the  convoluted  tubules  in  the  laby- 
rinth are  wide,  and  the  projecting  epithelium  lining  them  is  somewhat 
swollen.  The  glomeruli  do  not  completely  fill  the  capsular  spaces ; 
in  some  of  the  latter  coagulated  albumen  may  be  seen.  Some  of  the 
tubules  in  the  medullary  rays  contain  in  their  lining  epithelium 
yellowish  pigment.  The  kidney  is  almost  free  from  malarial  organ- 
isms and  from  malarial  pigment,  although  occasionally  a  brownish- 
black  particle  is  visible  in  a  glomerulus. 

The  Mesenteric  Lymph  Glands. — The  lymph  sinuses,  especially  in 
the  medulla,  are  wide  and  are  filled  with  cells.  These  cells  for  the 
most  part  irregular  in  shape  contain  vesicular  nuclei  and  an  abundant 
protoplasm  which  stains  in  eosin  and  they  resemble  in  general  the 
endothelial  cells  which  normally  lie  upon  and  are  wrapped  around  the 
reticular  framework.  There  are  also  many  large  and  small  lympho- 
cytes and  a  few  red  blood-corpuscle-carrying  cells.  Some  cells  like 
those  filling  up  the  lymph  sinuses  can  be  seen  among  the  lymphoid 
cells  in  the  lymph  follicles  and  cords.  They  occasionally  contain 
within  their  protoplasm  malarial  organisms  and  their  remains. 

This  case,  it  would  seem,  may  be  of  help  in  explaining  the  relation 
of  malaria  to  cirrhosis  of  the  liver  and  allied  diseases. 

Even  in  the  early  descriptions  of  malaria  the  important  influence 
of  the  disease  as  a  causative  factor  in  the  production  of  chronic  inter- 
stitial inflammations  of  some  of  the  internal  organs,  and  especially  of 
the  liver  and  kidneys  is  mentioned.  Frerichs  and  Lanceraux  both 
believed  in  a  chronic  hepatitis  of  paludal  origin.  Kelsch  and  Kiener 
working  at  the  disease  without  any  appreciation  of  the  importance  of 
the  malarial  parasites  laid  stress  upon  the  changes  in  the  liver  secondary 
to  malaria  and  describe  both  parenchymatous  and  interstitial  forms 
of  hepatitis.  They  refer  to  three  varieties  of  the  latter  and  discuss  at 
length  the  character  and  distribution  of  the  lesions  in  the  liver.  These 
same  authors  describe  two  main  types  of  chronic  disease  of  the  kidneys 


A  Study  of  Some  Fatal  Cases  of  Malaria.  25 

dependent  upon  malaria,  the  first,  a  diiFuse  malarial  nephritis  or  glo- 
merulo-nephritis,  and  the  second,  a  nephritis  characterized  by  a  small 
granular  kidney.  Bartels,  Rosenstein,  Bouillaud,  and  others  had 
early  referred  to  the  relation  existing  between  malaria  and  chronic 
disease  of  the  kidney.  Laveran  emphasised  a  chronic  interstitial 
pneumonia  of  malarial  origin,  and  Durozier  in  1870,  and  also  Kelsch 
and  Kiener  referred  to  the  frequent  occurrence  of  vegetative  or  ulcera- 
tive endocarditis  in  chronic  malaria  and  believed  that  the  lesions 
of  the  heart  valves  might  be  directly  referable  to  the  action  of  the 
malarial  poison.  Finally,  chronic  degenerative  and  fibroid  processes 
in  the  spinal  cord  and  brain  have  been  attributed  by  some  authors 
to  malaria. 

On  the  other  hand,  by  not  a  few  authors  the  possibility  of  cirrhotic 
processes  being  due  to  malaria  has  been  stoutly  denied.  It  has  been 
justly  claimed  that  in  many  of  the  cases  reported  as  instances  of 
chronic  inflammation  due  to  malaria  insufficient  attention  has  been 
paid  to  the  possible  responsibility  of  other  etiological  factors,  such 
as  alcoholism,  syphilis,  and  tuberculosis. 

Dr.  Osier  has  particularly  pointed  out  the  difficulty  of  saying  in  a 
given  case  of  cirrhosis  of  the  liver  or  kidneys  that  malaria  has  been 
the  cause,  and  in  his  experience  the  association  of  malaria  with  cir- 
rhosis has  been  very  uncommon.  Dr.  Welch  has  seen  only  one  case 
of  malarial  cirrhosis  of  the  liver  in  New  York,  and  that  was  in  an 
Algerian. 

The  foregoing  study  has,  however,  convinced  me  that  there  are 
conditions  present  in  malaria  which  are  generally  recognized  as  being 
capable  of  giving  rise  to  chronic  fibroid  processes,  and  it  would  be 
strange  did  the  latter  not  occur  more  or  less  frequently.  Bignami 
in  a  very  careful  study  of  chronic  malarial  cases  in  Italy  has  come  to 
a  similar  conclusion  and  traces  with  much  acumen  the  chain  of  events 
from  the  onset  of  an  acute  malarial  infection  to  the  development  of  a 
cirrhotic  process. 

A  careful  consideration  of  the  various  phenomena  associated  with 
acute  malaria  will  show  that  there  are  many  ways  in  which  a  chronic 
interstitial  inflammation  could  arise.  Thus  looking  upon  the  chronic 
interstitial  inflammations  as  being  due  most  often  to  a  primary  de- 
generation of  certain  of  the  tissue  elements,  the  new  growth  of  fibrous 
tissues  being  secondary,  we  can  think  of  many  possible  causes  of  the 


26  ,  Leioellys  F.  Barker. 

former.  Thus,  the  profound  changes  in  the  character  of  the  blood 
serum  consequent  upon  the  alteration  and  destruction  of  large  numbers 
of  red  blood  corpuscles  and  leucocytes,  the  intermittent  hyperemia  in 
the  viscera,  the  setting  free  of  the  malarial  pigment,  and  the  accumu- 
lation of  the  latter  in  the  cells  and  tissues,  the  multiple  capillary 
thromboses  which  sometimes  occur,  the  disturbances  of  digestion  in 
many  of  the  cases,  the  areas  of  necrotic  cells  which  can  be  demon- 
strated in  liver  Spleen  and  kidneys,  these  are  sufficient  to  convince 
one  of  the  existence  of  many  possible  injurious  influences. 

The  evidences  in  favor  of  the  idea  that  the  parasites  produce  definite 
toxines  and  that  large  quantities  of  these  are  set  free  during  segmen- 
tation after  each  paroxysm  is  already  considerable.  The  clinical 
phenomena  in  general  and  especially  the  increased  toxicity  of  the 
urine  after  the  paroxysm  would  seem  to  point  to  this.  It  must  be 
remembered,  however,  that  as  yet  no  toxine  has  been  proven  to  be 
formed  by  the  parasite.  It  matters  little,  however,  whether  the  toxic 
substances  are  produced  by  the  parasites  directly,  or  are  in  part  the 
indirect  result  of  their  action  upon  the  red  blood  corpuscles,  the  white 
cells  or  tissue  juices.  There  is  sufficient  evidence  that  some  toxic  agent 
is  at  work.  The  cloudy  swelling  seen  in  the  organs,  the  fever,  the 
acute  splenic  tumor,  but  more  especially  the  actual  necroses  early 
demonstrable  under  the  microscope,  make  it  impossible  to  doubt 
this  fact. 

In  our  description  of  Case  C  we  have  referred  to  the  extensive 
focal  necroses  in  the  liver  and  in  the  spleen.  Single  cells,  small  groups 
of  cells  and  quite  large  areas  of  cells  were  found  in  a  state  of  hyaline 
necrosis  where  the  nuclei  refused  to  stain  and  the  protoplasm  showed 
an  increased  affinity  for  acid  dyes.  In  such  necrotic  areas  numerous 
cells  were  present,  some  of  them  leucocytes  with  polymorphous  nuclei, 
others  small  mononuclear  cells.  In  some  of  the  older  ones  spindle- 
shaped  cells  could  be  seen.  Fragmentation  of  nuclei  and  phagocytosis 
were  visible,  and  there  were  multiple  capillary  thrombi  to  be  made 
out.  We  have  referred  to  the  extensive  necroses  of  the  spleen  pulp 
cells,  of  the  red  blood  corpuscles  and  of  the  leucocytes.  In  many 
bacterial  infections  similar  areas  of  necrosis  have  been  proven  to  be 
due  to  the  toxines  which  the  bacteria  produce.  Reed  for  typhoid 
fever  and  Welch  and  Flexner  for  diphtheria  have  shown  that  the 
soluble  products  of  the  bacilli  alone  circulating  in  the  blood  are 


A  Study  of  S&me  Fatal  Cases  of  Malaria.  27 

capable  of  giving  rise  not  only  to  diffuse  parenchymatous  changes, 
but  also  to  definite  focal  lesions,  areas  of  cell-death  of  varying  size. 
Later  Flexuer,  experimenting  with  blood  serum,  has  shown  that 
the  serum  of  one  animal  will  produce  focal  necroses  in  the  liver 
kidney  and  spleen  of  an  animal  of  a  different  species  when  injected 
intravenously  into  the  latter.  He  further  proved  that  these  focal 
necroses  could  later  result  in  the  production  of  chronic  interstitial 
processes  in  the  liver  and  kidney. 

In  the  liver,  following  the  necroses,  there  was  such  an  accurate  repro- 
duction of  the  cirrhosis  seen  in  human  beings  that,  as  he  put  it,  "a 
separate  description  seems  superfluous."  Areas  of  newly  formed  and 
forming  connective  tissue  proceeded  from  the  portal  spaces,  and  also 
from  the  capsule ;  these  were  irregularly  distributed  throughout  the 
organ.  Newly  formed  bile  ducts  were  numerous ;  but  what  was  of 
particular  moment  was  the  association  with  these  of  another  process, 
namely,  acute  degenerative  changes  in  the  liver  substance  which  were 
distinctly  to  be  recognized  as  the  starting  places  of  the  cirrhotic 
processes.  "  The  necroses  and  disintegration  of  the  liver  cells  with 
emigration  of  the  leucocytes  went  directly  over  into  the  new  growth 
of  fibrous  tissue.  New  fibrous  tissue  could  be  formed  within  lobules, 
apparently  independently  of  the  iuter-lobular  connective  tissue  and 
of  the  capsule,  just  as  there  are  independent  foci  of  necroses  in  this 
situation." 

It  is  easy  to  understand  how  the  normal  serum  of  the  individual 
could  be  altered  by  the  disease  so  as  to  become  definitely  toxic.  Aside 
from  the  increased  toxicity  of  the  serum  due  to  the  presence  of  malarial 
toxines,  the  destruction  of  large  numbers  of  red  blood  corpuscles  and 
the  setting  free  of  young  parasites,  of  pigment,  and  of  masses  of  haemo- 
globin, cannot  fail  to  be  of  considerable  import.  And  although  there  is 
no  experimental  evidence  bearing  on  this  point,  it  is  not  impossible  that 
the  isotonie  of  the  blood  serum  could  be  so  affected  as  to  lead  to  serious 
alterations  not  only  in  the  constituents  of  the  blood  but  also  in  the 
cells  of  the  organs.  That  haemoglobinaemia  and  haemoglobinuria 
occur  sometimes  in  malaria  is  well  known.  Haemoglobinaemia  alone 
can  give  rise  to  an  acute  splenic  tumor,  or  to  an  acute  nephritis,  as  is 
well  known  in  cases  of  poisoning  by  the  chlorate  of  potassium  and  in 
the  intoxication  of  one  animal  by  the  blood  serum  of  an  animal  of  a 
different  species.    The  alterations  in  the  functions  of  the  spleen,  liver, 


28  Lewellys  F.  Barker. 

and  alimentary  canal  could  easily  lead  also  to  important  changes  in 
the  blood  serum. 

The  relations  of  the  melanaemia  to  cirrhotic  processes  is  worth 
considering.  The  malarial  pigment  tends  to  accumulate  in  the  peri- 
phery of  the  hepatic  lobules  and  in  the  trabeculae  of  the  spleen.  It 
remains,  too,  for  some  time  after  the  infection  has  disappeared,  and 
it  is  not  impossible  that  the  irritation  caused  by  the  presence  of  this 
pigment  could  give  rise  to  a  chronic  interstitial  inflammation,  perhaps 
analogous  to  the  pneumonoconioses.  It  seems  less  probable,  however, 
that  the  pigment  is  responsible  for  a  new  growth  of  fibrous  tissue  than 
that  the  latter  is  secondary  to  degeneration  due  to  toxic  effects. 

It  has  been  generally  believed  that  any  pathological  condition  which 
leads  to  an  intermittent  hyperemia  of  an  organ  may  give  rise  to  a 
chronic  interstitial  inflammation.  In  malaria  there  can  be  but  little 
doubt  that  there  is  variable  hyperemia  of  the  liver  and  spleen  with 
the  paroxysms,  just  as  the  size  of  the  spleen  and  liver  varies  in  re- 
current attacks  of  malaria. 

The  capillaries  in  the  liver  spleen  and  kidney  are  frequently  found 
dilated  especially  in  certain  areas.  Whether  this  is  at  all  dependent 
on  the  distribution  of  the  makrophages  it  is  difficult  to  say. 

Finally  the  influence  of  the  disturbances  of  the  digestive  processes  in 
malaria  must  not  be  omitted  in  considering  the  etiology  of  cirrhotic 
inflammations.  There  is  general  obstruction  in  the  tributaries  of  the 
portal  vein,  and  this  alone  would  suffice  to  materially  alter  the  as- 
similation. But  in  addition,  as  we  have  seen,  the  vessels  of  the  mucous 
membrane  of  the  stomach  and  intestines  may  be  occluded  in  certain 
cases  by  thrombi  of  parasites  or  of  infected  red  corpuscles.  In  some 
instances  the  nutrition  may  be  so  interfered  with  that  the  mucous 
membrane  becomes  necrotic.  Undoubtedly  in  such  instances  substances 
absorbed  from  the  lumen  of  the  alimentary  canal  are  far  from  normal. 

There  can  be  no  doubt,  considering  the  comparative  rarity  of  cir- 
rhosis following  malaria,  that  the  individual  pre-disposition  must  be 
an  important  factor  in  those  cases  in  which  it  occurs.  Associated  alco- 
holism or  arterio-sclerosis  for  example  might  render  the  tissue  cells 
less  resistant  to  the  poisonous  substances,  whatever  they  may  be,  or 
prevent  the  normal  processes  of  repair. 

That  there  may  be  different  kinds  of  cirrhosis  of  the  liver  following 
malaria  is  not  impossible.     Thus  there  was  no  obvious  relation  in 


A  Study  of  Some  Fatal  Cases  of  Malaria.  29 

Case  C  between  the  enormous  increase  in  round  cells  in  the  portal 
spaces  and  the  focal  necroses  or  the  capillary  thrombosis.  Nor  was 
there  any  evidence  that  the  round  cells  were  being  converted  into 
fibrous  tissue.  Still  these  collections  were  quite  like  those  which  one 
sees  in  fresh  nodules  of  cirrhosis  of  the  liver.  Dock  has  observed  a 
similar  extensive  perivascular  portal  infiltration  in  a  very  acute  case 
of  malaria  in  a  young  man. 

V. 

Case  D. — Double  tertian  malarial  infection,  associated  with  general 
streptococcus  infection  ;  symptoms  of  an  acute  nephritis  with  general 
anasarca  manifested  during  life.  Remarks  on  the  bacterial  in- 
fections and  protozoan  invasions  tohich  may  be  concurrent  with 
malaria. 

Abstract  of  clinical  record.     (Prof.  Osier.) 

L.  W.,  aet.  23,  oysterman,  married,  admitted  January  9th,  1892, 
complaining  of  shortness  of  breath  with  general  dropsy.  Family 
history  unimportant.  Patient  has  been  previously  healthy;  denies 
syphilis ;  gonorrhoea  nine  years  ago.  Has  never  used  alcohol  in 
excess.  Some  three  months  before  entrance,  his  work  required  him 
to  stand  in  cold  water  daily  for  about  two  weeks.  At  the  end  of  this 
time  he  noticed  that  his  feet  and  body  began  to  swell,  that  his  urine 
was  scanty  and  high-colored,  sometimes  even  bloody,  and  that  fre- 
quently he  had  to  rise  two  or  three  times  during  the  night  to  urinate. 
Somewhat  later  he  observed  that  he  was  becoming  short  of  breath, 
especially  on  exertion.  Three  weeks  before  admission  he  had  a  severe 
shaking  chill,  the  first  during  his  illness,  and  for  the  next  two  weeks 
he  had  chills  nearly  every  day.  During  the  past  week,  he  states 
that  he  has  had  no  chills.  The  dropsy  has  gradually  increased,  and 
the  dyspnoea  has  become  progressively  more  intense.  Of  late  the 
urine  has  not  been  bloody,  and  the  amount,  he  thinks,  is  larger  than 
formerly. 

Temperature  on  admission,  97.8°.  Pulse  under  100.  Anasarca 
general.  Patient  rather  dull  and  stupid.  Pilocarpine  ^  gr.  hypo- 
dermically  repeated  once  caused  profuse  sweating. 

Note  dictated  October  1, 1892. — "Medium  sized  man  of  good  muscu- 
lature ;  lips  and  mucous  membranes  a  little  pale ;  tongue  coated  ;  face 


80  Lewellys  F.  Barker. 

much  swollen ;  feet  and  legs  oedematous.  Abdomen  a  good  deal 
distended.     Respirations,  24;  pulse,  84. 

Thorax. — Percussion,  resonance  good  in  front ;  deficient  behind  at 
i^ight  base  where  vocal  fremitus  is  absent  and  the  respiration  is  distant. 
On  auscultation  the  sounds  are  clear  in  front;  behind  and  in  the 
axillse  numerous  fine  rales  are  audible.  Heart  sounds  clear  at  apex 
and  base. 

Liver  dulness  merges  almost  directly  into  colon  tympany  at  the 
7th  rib.  Splenic  dulness  begins  at  the  8th  rib.  Though  uniformly 
distended  the  abdomen  is  tympanitic  and  no  movable  dulness  can 
be  obtained. 

Urine. — Dark  in  color,  1000  cc.  in  amount.  Sp.  gr.,  1017 ;  albumen 
abundant ;  many  hyaline,  darkly  granular  and  epithelial  casts  present." 

This  case  was  looked  upon  clinically  as  one  of  acute  nephritis.  The 
existence  and  character  of  the  fever  were  noted  as  unusual. 

Dr.  Osier,  in  commenting  on  the  case  in  clinic,  alluded  to  the  ex- 
istence of  the  fever,  the  mode  of  onset,  and  to  the  occurrence  of  chills, 
and  stated  that  the  existence  of  malaria  was  negatived  by  the  absence 
of  Plasmodia  from  the  blood.  Unfortunately,  through  a  misunder- 
standing among  the  assistants,  each  believing  that  the  other  had  looked 
for  the  parasites,  no  examination  of  the  blood  had  been  made. 

By  January  23rd,  the  patient  had  become  more  oedematous.  The 
pulse  was  140 ;  fluid  was  now  demonstrable  in  the  right  pleural  sac 
and  in  the  peritoneal  cavity.  The  urine  still  contained  large  quantities 
of  albumen  and  casts.  The  fever  persisted  and  was  rather  remittent 
in  type  ranging  between  99°  and  104°  F.  Hot  baths,  diluents  and 
diuretics  were  given. 

On  the  24th  and  25th  the  patient  was  much  worse,  took  nourishment 
badly ;  the  respirations  were  rapid  and  the  pulse  was  feeble.  The 
general  anasarca  became  extreme  and  there  was  marked  conjunctival 
oedema.  The  heart  sounds  remained  clear  throughout  the  whole 
course  of  the  disease.  Death  occurred  on  the  26th  of  January,  seven- 
teen days  after  admission. 

Autopsy.     (Dr.  Councilman.) 

Anatomical  Diagnosis. — Acute  malarial  fever ;  general  streptococcus 
infection ;  subacute  Bright's  disease;  malarial  pigmentation  of  organs ; 
chronic  passive  congestion  ;  general  anasarca ;  infarctions  of  kidneys  ; 
erysipelas. 


A  Study  of  Some  Fatal  Cases  of  Malaria.  31 

Body  of  strongly  built  light  mulatto ;  face  and  neck  markedly 
oedematous ;  livor  mortis  in  dependent  parts ;  general  subcutaneous 
oedema ;  scrotum  markedly  swollen.  On  the  left  shoulder,  and  on 
the  inner  aspect  of  both  thighs  there  are  blebs  containing  clear  straw- 
colored  liquid  surrounded  by  areas  of  reddish  discoloration. 

The  peritoneal  cavity  contains  about  one  litre  of  straw-colored  fluid, 
which  contains  large  soft  clots.  The  pleural  cavities  also  contain  a 
considerable  amount  of  serous  fluid. 

Heart  of  medium  size,  chambers  contain  fluid  blood  and  soft  clots ; 
weight,  300  grams ;  myocardium  dark  reddish-brown  in  color ;  all 
valves  normal.  Aorta  abnormally  small  and  thin,  measuring  in  cir- 
cumference, just  above  valves,  4.5  cm. ;  at  middle  of  thoracic  aorta, 
4  cm. ;  at  diaphragm,  4  cm. ;  at  bifurcation,  2.75  cm.  The  common 
iliac  vessels  measure  2  cm.  in  circumference;  the  left  subclavian,  1.9 
cm. ;  the  innominate,  2.5  cm.     Pulmonary  artery  normal. 

The  Lungs. — The  surfaces  of  both  are  smooth,  and  both  are  crepi- 
tant throughout.  The  consistence  is  increased,  color  dark  red,  moderate 
coal-pigm  entation . 

The  iiver.— Weight,  1600  grams;  dimensions,  25  x  16  x  8  cm.; 
Surface  smooth  ;  exquisite  outlining  of  lymphatic  network  on  surface. 
Consistence  about  normal.  Color  on  section  dark  chocolate-brown 
color.     Lobules  visible. 

The  Spleen  is  small,  weighs  only  100  grams;  size,  12  x  7  x  3 
cm.;  capsule  smooth,  not  much  thickened;  consistence  very  firm. 
On  section  the  substance  is  almost  black,  of  a  much  darker  tint  than 
the  liver.  The  Malpighian  bodies  are  not  visible.  The  trabeculae 
are  visible  and  apparently  increased  in  thickness. 

The  Kidneys  together  weigh  400  grams.  They  are  both  alike  in 
size  and  general  appearance.  On  the  surface  of  each  a  few  small  fresh 
infarctions  with  hemorrhagic  margins  are  visible.  The  capsules  strip 
off  easily.  The  general  color  of  the  external  surfaces  of  the  kidneys 
beneath  the  capsules  is  yellowish-brown,  marked  by  scattered  opaque 
darker  areas,  and  here  and  there  by  minute  hemorrhages.  The  whole 
kidney  has  a  rather  soft  oedematous  feel.  On  section  the  cortex  has 
a  yellowish  appearance  and  is  rather  translucent ;  pyramids  reddened, 
contrasting  sharply  with  the  lighter  colored  cortex.  On  some  parts 
of  the  cortex  the  striae  are  well  marked,  in  others  they  are  less  apparent 
or  invisible.     Average  width  of  cortex  1  cm,     A  small  amount  of 


32  Lewellys  F,  Barker. 

fluid  exudes  from  the  cortical  substance  on  pressure.  The  glomeruli 
are  indistinct.  The  pancreas  is  oedematous.  The  adrenal  glands 
are  normal  in  size  but  it  is  noticeable  that  they  are  darker  in  color 
than  normal. 

The  stomach  is  moderately  dilated ;  both  it  and  the  intestines  con- 
tain an  excess  of  mucus.  The  intestines  are  generally  distended  and 
their  walls  are  oedematous. 

The  bone-marrow  is  intensely  pigmented,  reddish-brown  in  color. 
The  brain  is  small,  especially  in  the  frontal  regions ;  weight,  940 
grams.  The  pia  is  firmly  adherent.  No  marked  pigmentation.  No 
hemorrhages  or  focal  disease. 

The  Blood. — Examined  fresh  from  the  peripheral  veins  and  various 
internal  organs  showed  enormous  numbers  of  malarial  parasites,  most 
of  them  nearly  full  grown,  others  only  half  grown  (tertian  type),  many 
of  them  enclosed  within  the  protoplasm  of  large  mononuclear  leuco- 
cytes.    No  flagella  seen. 

Frozen  Seetions  of  the  kidney  show  a  very  little  fat  in  fine  droplets 
in  the  glomeruli.  The  epithelial  cells  of  the  tubules  in  the  labyrinth 
are  much  swollen  and  are  filled  with  fine  albuminous  granules  and 
hyaline  droplets. 

Many  of  the  tubules  are  dilated  and  are  lined  by  low  epithelium. 
Casts  are  numerous  in  sections  and  in  urine  collected  from  the  bladder. 
Coagulated  albumen  is  visible  in  the  capsular  spaces,  in  frozen  sections 
made  from  bits  of  kidney  previously  fixed  in  boiling  water.  The 
capsular  epithelium  is  swollen  and  evidently  proliferated. 

Bacteriological  Examination.     (Dr.  Flexner.) 

Cover  slips  from  the  heart's  blood  prepared  and  stained  in  the 
ordinary  way  showed  numerous  chains  of  streptococci. 

Cultures. — At  the  autopsy,  the  surface  of  the  organs  was  burned  with 
a  hot  knife,  punctured  through  the  burned  area,  and  tubes  of  agar- 
agar  were  inoculated  from  the  internal  tissues.  Esmarch  roll-tubes 
were  employed ;  after  being  kept  in  the  thermostat  for  twenty-four 
hours  at  37°  C  they  were  examined  with  the  following  results  :  The 
tube  from  the  lung  was  found  to  be  closely  crowded  with  extremely 
minute  colonies  of  streptococci,  no  other  micro-organisms  being  present. 
The  heart's  blood,  kidney,  liver,  bone-marrow  and  spleen  all  yielded 
many  colonies  of  streptococci,  here  also  in  pure  cultures.  The  tube 
from  the  spleen  contained  many  more  colonies  than  that  from  the  liver. 


A  Study  of  Some  Fatal  Cases  of  Malaria.  33 

The  tube  inoculated  from  the  bile  contained  a  few — about  one  dozen — 
colonies  of  streptococci.  Tubes  were  also  inoculated  from  the  fluid 
in  the  erysipelatous  blebs  and  from  the  ©edematous  subcutaneous 
tissue  at  their  margins.  In  those  from  the  latter  a  pure  culture  of 
streptococci  was  obtained. 

Microscopical  Examination.— The  Liver.— In  sections  examined 
with  very  low  powers  (8  to  16  diameters),  it  is  easy  to  make  out 
dilatations  of  the  central  and  sublobular  veins  and  of  the  capillaries 
about  the  central  veins,  and  also  that  the  large  amounts  of  dark 
malarial  pigment  which  are  present  are  rather  peculiarly  distributed. 
Instead  of  being  most  abundant,  as  is  ordinarily  the  case,  according 
to  those  who  have  examined  large  numbers  of  malarial  livers,  at  the 
periphery  of  the  lobules,  in  this  instance  the  pigment  is  situated  in 
more  or  less  well-marked  zones  which  correspond  nearly  to  the  outer 
limits  of  the  areas  of  dilated  capillaries.  Small  amounts  of  pigment 
press  into  the  areas  of  capillary  dilatation,  and  some  pigment  can  be 
seen  in  the  parts  of  the  lobules  in  which  the  capillaries  are  not  dilated, 
but  the  great  bulk  of  the  pigment  is  certainly  present  in  the  zones 
described.  The  portions  of  the  lobules  nearest  the  central  veins,  and 
those  nearest  the  peripheries  are  comparatively  free  from  malarial 
pigment. 

On  examination  with  higher  powers,  the  black  and  brownish-black 
malarial  pigment  is  seen  to  be  chiefly  included  by  large  makrophagic 
cells  within  the  liver  capillaries,  and  it  is  to  the  accumulation  of  these 
cells  in  the  zone  previously  described,  that  the  peculiar  distribution 
of  the  pigment  as  seen  with  very  low  powers  must  be  attributed. 
These  large  cells  in  which  by  far  the  greater  portion  of  the  malarial 
pigment  is  contained,  vary  considerably  in  size  shape  and  general 
appearance.  The  smallest  ones  correspond  in  size  to  the  ordinary 
mononuclear  leucocytes,  the  largest  reach  the  size  of  giant  cells,  and 
are  equal  in  bulk  to  three  four  or  more  times  that  of  the  smaller  ones. 
Between  these  two  limits  there  are  many  intermediate  sizes.  Many 
of  the  cells  have  round  smooth  margins,  others  are  polyhedral,  many 
are  oval  or  ovate  in  shape.  These  cells  usually  contain  a  single  round, 
or  more  often  an  oval  vesicular  nucleus;  sometimes  two  vesicular 
nuclei  are  present.  The  protoplasm  of  these  cells,  when  not  too  much 
obscured  by  included  substances,  can  be  seen  to  take  a  feeble  stain  in 
haematoxylin  and  often  to  contain  larger  and  smaller  vacuole-like 


34  Lewdlys  F.  Barker. 

spaces,  some  of  which  may  represent  fat  droplets.  But  as  a  rule  the 
protoplasm  is  scarcely  visible,  owing  to  the  presence  of  the  large 
accumulations  of  extraneous  substances  and  structures  which  have 
been  included  within  it.  It  was  somewhat  puzzling  at  first  to  decide 
as  to  the  exact  nature  of  the  different  contents  of  these  cells.  In  thick 
sections  the  protoplasm  appears  to  be  filled  simply  with  coarse  irregular 
masses  of  black  and  blackish-brown  malarial  pigment,  but  in  thin 
sections  and  by, various  modifications  in  the  staining  technique  it  is 
possible  to  distinguish  easily  a  number  of  different  morphological 
elements.  In  the  largest  cells,  the  protoplasm  of  which  is  crowded 
with  black  pigment,  it  can  be  made  out  that  most  of  the  pigment  does 
not  exist  in  irregular  blocks  (although  some  apparently  does),  but  in 
definite,  more  or  less  regularly  spherical  masses.  Often  there  is  an 
appearance  as  though  a  malarial  organism,  which  has  been  included, 
had  suffered  rupture  of  its  capsule,  allowing  the  partial  escape  of  the 
pigment.  From  the  shrunken  malarial  capsules  (in  which  the  pig- 
ment exists  usually  as  a  more  or  less  fused  and  homogeneous  mass, 
rather  than  as  distinct  granules  as  seen  in  the  well  preserved  organisms) 
delicate  dotted  lines  of  minute  pigment  particles  can  be  seen  running 
in  different  directions  out  into  the  protoplasm  of  the  phagocytes. 
Occasionally  in  these  very  large  cells,  much  more  often  in  the  smaller 
ones,  well  developed  spherical  tertian  malarial  organisms,  with  pig- 
ment granules  arranged  in  lines  in  their  peripheries  and  central  non- 
pigmented  areas  can  be  seen.  The  number  of  included  organisms  and 
shrunken  capsules  (cadavers,  corpses,  or  debris  of  malarial  organisms), 
is  often  large.  As  many  as  twenty  and  even  thirty  were  counted  in 
some  cells,  and  doubtless  a  number  of  the  very  large  cells,  where  the 
bodies  lie  closely  crowded  in  different  planes  so  that  they  can  be 
counted  only  with  great  difficulty,  contain  even  greater  numbers  of 
them.  Dark  brownish-black  pigment  in  little  clumps,  resembling  that 
seen  near  the  centers  of  segmenting  tertian  organisms,  is  also  observed 
within  these  cells,  and  part  of  the  irregular  masses  of  malarial  pigment 
may  represent  aggregations  of  this  segmental  pigment. 

Included  in  many  of  these  large  cells  are  visible  red  blood  corpuscles, 
sometimes  only  one  or  two,  sometimes  large  numbers  of  them — true 
red  blood-corpuscle-carrying  cells.  There  are  also  numerous  irregular 
yellow  particles  and  masses  which  look  like  fragments  of  red  cor- 
puscles.    On  (or  in)  some  of  the  corpuscles  granules  of  malarial 


A  Study  of  Some  Fatal  Cases  of  Malaria.  35 

pigment  are  seen  infected  red  blood  corpuscles  (?).  In  specimens 
hardened  in  alcohol,  stained  with  alum-cochineal,  and  treated  with  a 
fresh  solution  of  ferrocyanide  of  potassium  to  which  a  little  pure  hy- 
drochloric acid  had  been  added,  very  instructive  views  of  the  contents 
of  these  makrophages  are  obtainable.  Many  of  the  yellow  particles 
and  masses  give  very  definitely  the  blue  haemosiderin  reaction,  and 
in  this  way  a  much  better  idea  of  the  number  of  partially  destroyed 
red  blood  corpuscles  present  can  be  gained.  The  fully  formed  in- 
traphagocytic  red  corpuscles  do  not  as  a  rule  give  the  haemosiderin 
reaction,  but  retain  their  yellowish  tint ;  some  of  them  indeed  are 
distinctly  brassy  in  appearance,  although  these  brassy  corpuscles  are 
by  no  means  so  numerous  in  the  liver  of  this  case  as  in  that  from  a 
case  of  an  aestivo-autumnal  infection.  Occasionally,  a  red  disc  of  full 
size  and  normal  shape  will  give  the  distinct  Berlin  blue  reaction,  and 
at  times  particles  of  malarial  pigment  can  be  seen  lying  on  such  a  blue 
disc.  A  great  many  of  the  fragments  of  corpuscles  do  not  yield  the  blue 
color  with  the  ferrocyanide  mixture,  so  that  in  the  large  cells  yellow 
corpuscles,  yellow  fragments,  blue  corpuscles  and  blue  fragments  lie 
mixed  in  varying  proportions,  along  with  altered  and  unaltered 
malarial  parasites  and  malarial  pigment. 

As  might  be  expected  in  cells  whose  protoplasm  is  burdened  with 
such  large  amounts  of  deutoplasm,  the  position  and  shape  of  the  nu- 
cleus often  deviate  widely  from  the  normal.  Nearly  always  placed 
excentrically,  the  nucleus  is  sometimes  pushed  to  the  extreme  margin 
or  end  of  the  cell,  and  instead  of  exhibiting  its  ordinary  oval  contour 
it  may  assume  a  stellate  or  more  often  a  crescentic  outline.  Sometimes 
indeed  the  nucleus  is  seen  to  be  fragmented,  or  to  be  absent  altogether, 
and  in  such  cells  the  protoplasm  has  a  swollen  glassy  appearance  and 
is  much  more  refractive  than  normal. 

Besides  the  malarial  organisms  and  their  remains,  blood  corpuscles 
and  their  derivatives,  many  of  these  edacious  cells  contain  within  their 
protoplasm  still  other  objects.  Thus  it  is  not  uncommon  to  see  inside 
them  one  or  more  white  blood  cells.  These  included  white  corpuscles 
usually  have  nuclei  of  the  lymphoid  type,  sometimes  they  have  poly- 
morphous nuclei ;  or  again  the  two  kinds  may  be  present  together 
lying  alongside  one  another  in  the  protoplasm  of  the  same  including 
cell.  Sometimes  these  incorporated  white  cells  contain  within  their 
protoplasm  well  preserved  malarial  organisms  or  free  pigment.  Their 
3 


36  Lewellys  F.  Barker. 

nuclei  as  a  rule  stain  sharply,  and  their  protoplasm  does  not  appear 
to  be  abnormal.  At  other  times  the  protoplasm  of  the  included  cells 
is  more  highly  refractive  than  normal,  and  has  a  clear  glassy  look; 
the  nuclei  may  be  fragmented  and  stain  intensely,  or  they  may  be 
entirely  necrotic  and  refuse  to  take  up  any  of  the  ordinary  nuclear 
dyes.  When  the  large  cell  is  necrosed  (hyaline  protoplasm,  fragmented 
or  non-staining  nucleus)  and  contains  within  it  white  blood  corpuscles, 
these  are  likely? to  be  leucocytes  with  polymorphous  nuclei. 

Finally  in  the  protoplasm  of  the  makrophages  (the  case  being  one 
of  general  streptococcus  infection)  cocci  occur  singly,  in  chains,  or  in 
groups  of  chains ;  sometimes  the  streptococci  lie  within  the  protoplasm 
of  included  white  blood  corpuscles. 

The  makrophages  above  described  lie  usually  close  to  the  walls  of 
the  capillaries  but  do  not  appear  to  have  any  organic  connection  with 
the  walls.  Sometimes  a  single  one  is  large  enough  to  practically  close 
the  lumen  of  a  capillary.  They  appear,  too,  to  be  lodged  quite  fre- 
quently at  the  junction  of  capillaries  and  to  cause  obstruction  to  the 
flow  of  blood. 

There  is  an  astonishingly  large  number  of  well  preserved  tertian 
malarial  organisms,  nearly  fully  developed,  present  in  the  liver.  A 
comparatively  small  proportion  of  these  apparently  uninjured  organ- 
isms are  free  in  the  blood  or  enclosed  simply  in  red  blood  corpuscles. 
The  majority  of  those  in  the  blood-vessels  are  enclosed  within  the 
protoplasm  of  the  large  mononuclear  leucocytes,  from  one  to  six  in  a 
cell,  and  a  few  within  the  protoplasm  of  leucocytes  with  polymorphous 
nuclei ;  although  in  these  latter  one  rarely  sees  more  than  one  or  two 
in  a  cell.  As  has  already  been  mentioned,  a  few  well  preserved  ma- 
larial parasites  are  found  among  the  contents  of  the  free  makrophages, 
and  as  will  be  pointed  out  later,  occasionally  uninjured  parasites  at 
the  same  stage  of  development  as  those  in  the  blood  are  discernible 
inside  the  endothelial  cells  lining  the  hepatic  capillaries.  All  these 
organisms  appear  to  be  of  the  same  size  and  present  very  much  the 
same  appearances.  They  are  nearly  full  grown  and  ready  for  seg- 
mentation ;  indeed  two  definite  segmenting  bodies  (central  pigment 
surrounded  by  minute  oval  hyaline  bodies)  were  seen  in  the  blood  in 
one  section  of  the  liver.  The  malarial  organisms  in  alcohol  sections 
in  this  case  studied  carefully  with  the  best  apparatus  are  seen  to  be 
tolerably  regular  spheres,  consisting  of  a  thin  peripheral  layer  in  which 


A  Study  of  8ome  Fatal  Cases  of  Malaria.  37 

all  the  pigment  is  included,  and  a  central  more  or  less  spherical  mass 
which  does  not  contain  pigment.     The  brownish-black  pigment  is 
not  always  irregularly  distributed  in  the  outer  layer,  but  in  favorable 
specimens  it  can  be  seen  to  have  a  definite  arrangement  in  lines,  with 
clear  spaces  between,  running  like  meridians  at  certain  intervals  in 
the  directions  of  the  poles.     Even  in  the  organisms  with  ruptured 
capsules  this  arrangement  can  sometimes  be  made  out.     The  central 
or  usually  slightly  excentric  spherical  non-pigmented  area  stains  in 
certain  basic  dyes,  often  quite  intensely  in  methylene  blue,  only  feebly 
and  often  not  at  all  in  haematoxylin  and  in  aqueous  magenta  (vide 
Spleen  Plate).     The  outer  layer  of  the  organism  in  which  the  lines 
of  pigment  run  takes  no  tint  with  these  dyes.     The  pigment  in  some 
organisms  tends  to  accumulate  toward  one  pole,  and  to  retract  from 
the  other.     This  morphology  of  the  organism  can  best  be  made  out 
in  the  larger  veins,  where  the  plasmodia  are  very  numerous.     The 
free  organisms  and  infected  red  blood  corpuscles,  like  the  leucocytes, 
have  a  tendency  to  collect  along  the  walls  of  the  veins,  where  in  this 
case  (there  being  a  leucocytosis  of  considerable  degree),  together  with 
the  leucocytes  large  phagocytic  cells  and  chains  of  streptococci,  they 
form  masses  of  considerable  size  clinging  to  the  venous  walls.     In 
some  of  the  veins,  however,  leucocytes  and  organisms  are  fairly  evenly 
distributed  among  the  red  corpuscles  throughout  the  lumina  of  the 
vessels.     Some  of  the  capillaries  and  smaller  veins  are  crowded  with 
cells   malarial   parasites   and  streptococci.     The  leucocytes  (mono- 
and  polynuclear)  scarcely  ever  contain  the  shrunken  remains  of  the 
parasites,  but  besides  the  well  preserved  forms  there  is  seen  in  them 
an  occasional  ruptured  organism,  segmental  pigment,  and  sometimes 
streptococci.     Here  and  there  the  nucleus  of  a  white  corpuscle  is  frag- 
mented, and  a  mononuclear  leucocyte  may  be  seen  enclosing  within  its 
protoplasm  a  lymphocyte  or  a  leucocyte  with  a  polymorphous  nucleus. 
The  spindle-shaped  endothelial  cells  lining  the  small  veins,  and 
especially  those  of  the  hepatic  capillaries,  present  interesting  appear- 
ances.    Many  of  them  contain  small  fragments  of  straw-colored  blood 
pigment,  and  in  the  protoplasm  of  some  of  them  malarial  pigment, 
malarial  organisms,  and  the  remains  of  parasites  are  included.     Some- 
times streptococci  are  to  be  seen  within  the  endothelial  cells.     The 
extraneous  matter  in  the  endothelial  cells  does  not  as  a  rule  greatly 
increase  their  bulk,  being  arranged  more  or  less  regularly  at  the  poles 


38  Lewdlys  F.  Barker. 

of  the  nuclei,  but  now  and  then  endothelial  cells  are  met  with  which 
are  much  swollen,  contain  large  masses  of  pigment  and  parasitic  re- 
mains, and  almost  obliterate  the  lumen  of  the  capillary.  Occasionally 
lymphoid  cells  or  polynuclear  leucocytes  are  seen  within  them.  Some 
of  the  endothelial  cells  have  hyaline  protoplasm  similar  to  that  de- 
scribed as  occurring  in  the  necrotic  makrophages. 

In  the  sections  stained  with  alum  cochineal  which  were  afterwards 
treated  with  the'acid  ferrocyanide  solution  and  examined  with  a  low 
power,  the  walls  of  the  capillaries  (more  marked  in  some  regions  than 
in  others)  are  seen  to  be  outlined  by  delicate  blue  pigment.  Exami- 
nation with  higher  powers  shows  this  to  be  haemosiderin  within  the 
protoplasm  of  the  capillary  endothelium.  Not  all  of  the  particles  of 
straw-colored  pigment,  however,  in  these  cells  yield  the  haemosiderin 
reaction  ;  while  in  some  of  the  cells  they  are  all  turned  blue,  in  others 
they  all  remain  yellow,  and  again  cells  are  seen  with  blue  and  yellow 
particles  mixed  in  varying  proportions. 

The  spaces  between  the  capillary  walls  and  the  liver  cells  are 
generally  exaggerated,  more  especially  towards  the  centers  of  the 
lobules.  The  cells  in  these  spaces  (Kupffer's  cells)  have  acted  as  pha- 
gocytes ;  they  are  swollen  and  exhibit  contents  analogous  to  those 
which  characterized  the  intra-capillary  makrophages.  The  swelling 
of  these  cells  in  some  places  has  been  so  great  as  to  press  the  ad- 
jacent capillary  wall  markedly  out  into  the  capillary  lumen.  The 
rows  of  liver  cells,  more  especially  those  about  the  central  vein,  are 
atrophied  and  are  narrow.  The  cells  contain  an  excess  of  yellow- 
brown  pigment;  the  nuclei  are  more  numerous  than  normal,  are 
shrunken  and  stain  intensely  in  nuclear  dyes.  There  are  very  few  actual 
necrotic  liver  cells  to  be  seen,  but  now  and  then  one  is  visible  containing 
a  fragmented  nucleus,  or  a  nucleus  which  does  not  stain  at  all.  The 
protoplasm  of  these  cells  is  hyaline  and  may  be  invaded  by  leucocytes 
with  polymorphous  nuclei.  The  liver  cells  do  not  contain  malarial 
organisms  or  pigment.  Much  of  the  yellowish-brown  pigment  within 
the  rows  of  liver  cells  yields  a  blue  reaction  with  Perl's  test.  In  some 
areas  the  actual  ectasis  and  liver  cell  atrophy  is  extreme.  In  those 
where  the  changes  in  the  liver  cells  are  the  same  the  capillaries  appear 
to  be  collapsed  and  the  number  of  nuclei  present  is  striking.  The 
liver  cells  of  the  peripheries  of  the  lobule  are  large  and  some  of  them 
contain  giant  nuclei.     In  the  connective  tissue  of  the  portal  spaces 


A  Study  of  Some  Fatal  Cases  of  Malaria.  39 

there  are  some  large  cells  filled  with  clumps  of  dark  malarial  pig- 
ment. There  is  a  slight  increase  in  the  number  of  lymphoid  cells 
in  these  spaces. 

Spleen. — The  comparatively  small  size  of  the  spleen  is  due  to  the 
existence  of  chronic  interstitial  changes.  On  microscopic  examination 
the  capsule  and  trabeculae  generally  are  found  to  be  much  thickened, 
and  there  is  thickening  and  fibrous  transformation  of  the  reticulum  of 
the  pulp.  The  spleen,  however,  also  shows  evidences  of  less  chronic 
lesions.  The  spleen-pulp  is  hyperaemic  and  there  is  a  marked  in- 
crease in  the  number  of  colorless  cells  in  the  pulp-cords  and  within 
the  splenic  veins  and  capillaries.  A  goodly  number  of  red  blood- 
corpuscle-carrying  cells  can  be  made  out.  While  some  of  these  cells 
contain  only  red  blood  corpuscles  as  inclusions,  in  others  are  also 
seen  malarial  parasites  and  pigment  together  with  some  nucleated 
white  cells. 

There  are  large  numbers  of  malarial  parasites  in  the  large  and  small 
splenic  blood-vessels,  exactly  similar  to  those  described  in  the  liver. 
Some  are  free  in  the  blood,  or  lie  on  or  in  infected  red  corpuscles ; 
the  majority  of  well  preserved  organisms  are  contained  within  the 
protoplasm  of  cells ;  there  are  from  one  to  six  in  each  of  the  cells, 
which  are  of  the  size  and  general  appearance  of  large  mononuclear 
leucocytes.  As  a  rule  the  nuclei  of  these  cells  stain  well,  but  oc- 
casionally they  do  not  take  the  dyes  at  all.  A  few  well  preserved 
organisms  and  some  free  brownish-black  (segmental?)  pigment  are 
to  be  seen  within  the  leucocytes  with  polymorphous  nuclei.  The 
nuclei  of  a  few  of  the  mononuclear  and  polynuclear  leucocytes  in  the 
splenic  capillaries  are  fragmented,  the  chromatin  being  broken  up 
into  deeply  staining  masses  of  varying  sizes. 

In  addition  to  these  cells  there  are  in  the  splenic  capillaries,  veins 
and  pulp,  many  makrophages,  large  usually  mononuclear  cells,  whose 
swollen  protoplasm  is  crowded  with  masses  of  malarial  pigment,  the 
shrunken  remains  of  malarial  organisms,  organisms  with  ruptured 
capsules,  and  occasionally  with  one  or  several  well  preserved  organ- 
isms in  the  same  stage  of  development  as  those  free  in  the  blood. 
These  cells  contain  in  addition  many  red  blood  corpuscles  and  frag- 
ments of  red  corpuscles,  part  of  which  yield  the  haemosiderin  reaction. 
On  some  of  the  included  red  corpuscles  particles  of  fine  malarial 
pigment  are  visible,  suggesting  that  these  corpuscles  when  received 


40  Lewellys  F.  Barker. 

into  the  phagocyte  were  infected  with  malarial  parasites.  These 
makrophages  may  contain,  like  those  in  the  liver,  white  cells,  and 
some  of  these  included  cells  may  contain  other  cells,  so  that  one  sees 
cell  within  cell  within  cell,  and  as  the  protoplasm  of  all  three  may 
contain  extraneous  substances,  one  may  speak  of  phagocyte  within 
phagocyte  within  phagocyte.  The  nuclei  and  protoplasm  of  including 
and  included  cells  vary  in  appearance — sometimes  the  former,  some- 
times the  latter  ^how  evidences  of  degeneration  or  necrosis.  Strepto- 
cocci are  very  abundant  throughout  the  spleen ;  they  appear  in  single 
chains  and  in  masses  of  chains.  They  are  especially  well  defined  in 
the  sections  stained  with  methylene  blue  and  eosin,  and  in  those  pre- 
pared according  to  Weigert's  method  for  the  differentiation  of  fibrin, 
bacteria  and  hyaline.  They  can  often  be  seen  enclosed  within  the 
protoplasm  of  cells,  mononuclear  and  polynuclear  leucocytes,  intra- 
vascular makrophages,  and  endothelial  cells.  Some  of  the  small 
veins  and  splenic  capillaries  are  actually  thrombosed  with  masses  of 
streptococci,  white  corpuscles,  malarial  organisms  and  phagocytes, 
matted  together  with  filaments  of  fibrin. 

The  endothelial  cells  in  the  spleen,  like  those  of  the  liver,  are 
swollen  and  contain  within  their  protoplasm  blood  pigment,  part 
of  which  has  been  transformed  into  haemosiderin.  A  few  of  them 
also  contain  malarial  organisms,  cadavers  of  parasites,  and  free  fine 
and  coarse  malarial  pigment ;  streptococci  may  be  seen  within  some 
of  them. 

A  certain  number  of  the  large  makrophages  within  the  splenic 
pulp  are  arranged  in  groups,  and  present  a  peculiar  appearance.  The 
cells  are  much  swollen,  and  besides  the  ordinary  contents  of  collapsed 
organisms  etc.,  large  areas  of  the  swollen  protoplasm  show  yellowish- 
brown  pigment  arranged  in  dotted  lines  ramifying  through  the  proto- 
plasm, which  is  often  hyaline,  so  that  we  have  something  which  looks 
like  tangled  masses  of  pigment  lines,  often  over-lying  and  hiding  the 
nucleus  from  view,  and  enclosing  minute  areas  of  hyaline  protoplasm 
within  the  felt-work  (vide  Plate  VI).  These  lines  of  pigment  often 
appear  to  run  out  from  the  pigment  masses  enclosed  within  the  cells. 
The  pigment  in  these  lines  when  in  focus  is  seen  to  be  dark  brownish- 
yellow  in  color,  while  that  out  of  focus  may  be  of  a  pale  straw  color. 
The  malpighian  corpuscles  of  the  spleen  are  somewhat  swollen  and 
are  almost  entirely  free  from  coarse  malarial  pigment.     On  close 


A  Study  of  Some  Fatal  Cases  of  Malaria.  41 

examination,  however,  fine  malarial  pigment,  yellowish-brown  in 
color,  arranged  often  in  lines,  and  not  enclosed  within  cells,  can  be 
made  out  in  many  of  the  malpighian  bodies  lying  in  the  interspaces 
between  the  lymphoid  cells. 

The  Kidney. — An  examination  of  many  glomeruli  shows  consider- 
able variation  in  the  size  of  the  capsular  spaces.     While  in  some 
instances  the  glomerulus  almost  completely  fills  out  Bowman's  capsule, 
the  space  being  a  mere  chink,  in  others  the  latter  is  equal  in  size  to 
one-third  of  the  whole  capsule.     The  space  is  not  always  empty  but 
may  contain  coagulated  albumin,  red  blood  corpuscles  and  shadows, 
or  a  few  mononuclear  cells  (desquamated  epithelium).     The  fibrous 
capsules  are  not  thickened  except  occasionally  where  an  atrophied 
glomerulus  is  visible.    Frequently  just  outside  the  capsule  of  Bowman 
a  narrow  clear  space  can  be  made  out,  and  this  may  contain  a  few 
cells,  chiefly  polyuuclear  leucocytes,  or  even  be  crowded  with  them. 
In  many  of  the  capsules  the  capsular  epithelium  is  evidently  pro- 
liferated, the  whole  inside  of  the  space  being  lined  by  nuclei  with 
intensely  staining  chromatin.     The  glomerular  capillaries  vary  in 
their  size  and  contents;  some  of  them  are  empty,  others  are  dis- 
tended.    Occasionally  one  is  seen  to  be  plugged  with  streptococci. 
The  number  of  white  corpuscles  within  the  glomerular  capillaries 
also  varies  ;  they  are  very  irregularly  distributed ;  in  some  glomeruli 
scarcely  any  are  present;  in  others  one  two  or  more  of  the  glomerular 
capillaries  may  be  packed  full  of  polynuclear  leucocytes.     In  a  section 
stained  in  methylene  blue,  a  capillary  is  visible  plugged  at  one  point 
with  streptococci  and  crowded  throughout  the  rest  of  its  extent  with 
leucocytes  with  polymorphous  nuclei, — reminding  one  forcibly  of  the 
appearance  of  the  capillary  glass  tubes  in  an  experiment  in  positive 
chemotaxis.     On  the  other  hand  masses  of  cocci  may  be  seen  with  no 
neighboring  leucocytic  accumulation.     The  nuclei  of  the  polynuclear 
leucocytes  vary  in  appearance ;  some  stain  sharply  and  take  on  the 
ordinary  forms ;  others  stain  less  sharply,  have  a  blurred  look  and 
assume  bizarre  shapes.     The  protoplasm  of  the  polynuclear  leucocytes 
frequently  contains  granules  or  minute  clumps  of  granules  of  malarial 
pigment,  occasionally  a  well-formed  parasite  or  short  chains  of  cocci. 
There  is  some  malarial  pigment  in  the  glomeruli  contained  within 
the  protoplasm  of  mononuclear  cells.     The  majority  of  the  malarial 
parasites  in  the  glomerular  capillaries  are  outside  nucleated  cells. 


42  Lewellys  F.  Barker. 

Here  and  there  in  specimens  stained  with  aqueous  magenta  a  giant 
spindle-shaped  nucleus  is  visible. 

The  lumina  of  the  convoluted  tubules  are  for  the  most  part  wide 
and  are  lined  with  rather  low  cubical  epithelium.  There  are  a  few 
areas  of  dilated  tubules,  in  which  the  lining  epithelium  is  flattened  so 
as  to  resemble  endothelium.  The  nuclei  of  the  epithelial  cells  as  a 
rule  stain  normally,  although  in  some  swollen  cells  they  stain  feebly, 
and  in  some  tubules  the  nuclei  are  shrunken  and  the  chromatin  stains 
more  intensely  than  normally. 

Many  of  the  convoluted  tubules  and  collecting  tubules  contain 
hyaline  casts ;  and  hyaline  droplets  are  visible  within  the  swollen 
lining  epithelial  cells.  These  droplets,  both  the  finer  and  the  coarser, 
and  the  upper  portions  of  the  hyaline  casts  stain  intensely  in  Weigert's 
fibrin  stain.  Occasionally  desquamated  epithelial  cells  and  a  few  red 
blood  corpuscles  and  round  yellowish  striped  urinary  concrements  are 
to  be  seen  within  the  lumiua  of  the  tubes. 

The  intertubular  capillaries  contain  enormous  numbers  of  strepto- 
cocci (methylene-blue,  Weigert's  fibrin  stain).  Many  of  them  are 
dilated  and  completely  plugged  with  cocci,  and  sometimes  chains  of 
cocci  are  visible  in  narrow  pericapillary  spaces.  As  in  the  glomerular 
vessels,  some  of  the  intertubular  capillaries  are  crowded  with  leuco- 
cytes. Some  of  the  small  veins  in  the  cortex  are  actually  thrombosed 
with  masses  of  streptococci,  large  numbers  of  malarial  parasites,  white 
corpuscles  (some  of  which  are  necrotic),  and  pigment  clumps.  No 
bacteria  other  than  streptococci  are  present  anywhere  in  the  kidney. 

In  the  interstitial  tissue  of  the  kidney  there  is  a  slight  but  evident 
increase  in  the  number  of  cells  of  the  lymphoid  type.  There  are 
small  nodal  masses  of  smaller  and  larger  round  cells,  usually  with  but 
little  perinuclear  protoplasm,  many  of  them  with  fragmented  nuclei. 
These  minute  nodes  may  contain,  besides  lymphoid  cells,  single  poly- 
nuclear  leucocytes  or  epithelioid  cells. 

Sections  of  the  kidney  treated  with  ferrocyanide  of  potassium  *  and 
hydrochloric  acid  show  an  almost  entire  absence  of  cells  containing 
haemosiderin.  Here  and  there,  however,  a  little  is  visible  within  the 
protoplasm  of  the  endothelium  of  the  vessels. 

The  infarcted  areas  of  the  kidney  present  the  lesions  ordinarily 
seen  under  these  circumstances — anaemic  necrosis  and  neighboring 
reaction.     The  whole  of  the  necrotic  area — glomeruli,  tubules,  blood- 


A  Study  of  Some  Fatal  Cases  of  Malaria.  43 

vessels,  interstitial  tissue — refuses  to  stain  in  the  ordinary  nuclear 
dyes,  and  has  an  increased  affinity  for  eosin.     The  only  nuclei  which 
stain  are  those  of  polynuclear  leucocytes  which  have  invaded  the  in- 
terstitial tissue  everywhere,  and  are  accumulated  in  large  numbers 
at  the  margins  of  the  infarcted  areas,  and  in  the  neighboring  dilated 
blood-vessels.    There  is  extensive  nuclear  fragmentation  in  these  poly- 
nuclear leucocytes,  and  the  most  varied  distortion-processes  (abschniir- 
uno-svorgange)  of  their  nuclei  are  visible.     Many  of  the  blood-vessels 
at  the  apices  and  in  the  peripheries  of  these  infarctions  are  thrombosed 
with  streptococci,  enormous  numbers  of  malarial  organisms,  over  100 
of  which  were  counted  inside  the  lumen  of  one  vessel,  and  white  cells. 
Small  bits  of  the  kidney  hardened  in  Flemming's  stronger  solution  and 
stained  with  aqueous  magenta  yield  very  instructive  sections.    Fine  fat 
droplets  are  visible  in  the  glomeruli  and  in  the  epithelium  lining  the 
capsular  spaces.     The  convoluted  tubules  are  not  extensively  fatty ; 
some  are  entirely  free  from  fat  droplets,  others  show  numerous  smaller 
and  larger  droplets,  especially  at  the  proximal  ends  of  the  lining  epithe- 
lial cells.    Fine  fat  droplets  are  also  visible  in  the  protoplasm  of  some 
of  the  leucocytes  in  the  vessels,  and  also  in  the  smooth  muscle  fibres  of 
the  arteries.     The  desquamated  epithelial  cells  within  the  lumina  of 
the  tubules  contain  numerous  rather  coarse  fat  droplets.     The  cells  of 
the  convoluted  tubules  in  sections  prepared  in  this  way  are  seen  to 
be  finely  granular  and  the  hyaline  degeneration  of  the  protoplasm  is 
well  shown.     Many  of  them  contain  large  vacuole-like  spaces  which 
sometimes  displace  the  nuclei.     In  some  of  the  tubes  free  red  blood 
corpuscles,  polynuclear  leucocytes,  and  malarial  organisms  are  visible. 
The  last  named  are  sometimes  free  or  lie  on  red  blood  corpuscles, 
sometimes  they  are  enclosed  within  cells.     They  are  to  be  seen  in 
both  polynuclear  and  mononuclear  cells  within  the  lumina  of  the 
convoluted  tubules.     In  one  tubule,  besides  numerous  red  blood  cor- 
puscles and  shadows,  four  free  well-fotmed  malarial  organisms  and  a 
mononuclear  cell  containing  within  its  protoplasm  five  malarial  or- 
ganisms of  the  same  stage  of  development  can  be  made  out.     Pictures 
such  as  these  were  seen  too  often  to  be  accounted  for  by  technical 
accidents.     Occasionally  red  corpuscles  malarial  parasites  and  white 
cells  are  visible  within  the  glomerular  capsular  spaces. 

The  Bone  Marrow. — The  malarial  parasites  in  the  marrow  are  for 
the  most  part  enclosed  within  mononuclear  cells ;  numerous  makro- 


44  LeweUys  F.  Barker. 

phages  are  here  present  with  contents  very  similar  to  those  described 
for  these  cells  in  the  spleen.  Streptococci  are  numerous,  some  free  in 
blood-vessels  others  enclosed  within  white  cells.  The  endothelial  cells 
contain  blood  pigment  at  the  poles  of  the  nuclei — part  of  which  yields 
the  blue  reaction.  There  is  an  increase  in  the  number  of  the  white 
cells  in  the  marrow,  and  a  considerable  number  of  nuclei  are  fragmented. 
Nucleated  red  blood  corpuscles  are  abundant,  as  are  also  degenerated 
red  corpuscles,  Qccurring  singly  and  in  clumps.  Some  of  the  strepto- 
cocci in  sections  treated  with  ferrocyanide  of  potassium  and  hydro- 
chloric acid  yield  a  sharp  blue  reaction,  so  that  the  chains  of  cocci 
look  as  though  stained  in  methylene  blue.  The  same  result  was 
obtained  with  some  of  the  cocci  in  the  spleen. 

The  Adrenal  Glands. — In  the  literature,  the  lesions  of  the  supra- 
renal capsules  in  malaria  have  not  received  the  attention  which  the 
findings  in  this  case  would  show  that  they  deserve.  The  arteries  and 
veins  of  the  capsule  are  wide  and  contain  many  malarial  organisms  as 
well  as  single  chains  and  masses  of  streptococci ;  the  lumina  of  some  of 
the  veins  are  completely  filled  with  accumulated  leucocytes  (mononu- 
clear and  poly  nuclear),  malarial  parasites  in  and  outside  of  red  cor- 
puscles and  streptococci.  A  few  makrophages  are  also  present  in  the 
veins  of  the  capsule.  There  are  irregular  areas  of  vascular  dilatation 
throughout  the  sections.  The  vessels  of  the  zona  glomerulosa  are 
generally  distended,  as  are  those  of  the  medulla ;  in  the  zona  fasci- 
culata  and  in  the  zona  reticularis  the  capillary  and  venous  dilatation 
occurs  in  areas.  It  will  be  remembered  that  in  the  liver  the  rows  of 
liver  cells  had  undergone  an  extent  of  atrophy  corresponding  to  that 
of  the  capillary  dilatation ;  similarly  here  in  the  area  of  capillary 
ectasis  the  adrenal  cells  are  small. 

Malarial  parasites  are  numerous  in  all  the  distended  vessels ;  many 
of  them  are  obviously  within  red  corpuscles,  a  large  number  are  en- 
closed mthin  the  protoplasm  of  mononuclear  leucocytes — from  one  to 
four  in  a  cell.  Polynuclear  leucocytes  are  numerous;  they  often  contain 
segmental  pigment  and  occasionally  a  malarial  organism.  The  ma- 
krophages, with  contents  like  those  in  the  liver  and  spleen,  are  present 
in  considerable  numbers  in  the  adrenal  capillaries,  being  somewhat 
irregularly  distributed  through  the  cortex  and  medulla ;  they  are  per- 
haps most  abundant  in  the  outer  portion  of  the  zona  fasciculata,  and 
fewest  in  the  zona  glomerulosa  which  is  tolerably  free  from  pigment 


A  Study  of  Some  Fatal  Cases  of  Malaria.  45 

masses  when  looked  at  with  very  low  powers  (8  and  16  diameters).  The 
endothelial  cells  are  phagocytic  here  as  in  the  liver,  their  nuclei  are 
large  and  vesicular,  their  protoplasmic  contents  quite  similar  to  those 
of  the  intra-capillary  makrophages,  except  that  they  consist  rather 
more  of  blood  pigment  and  less  of  malarial  pigment,  the  foreign 
substances  being  arranged  mainly  at  the  poles  of  the  nuclei.  Outside 
the  capillary  walls,  between  them  and  the  adrenal  cells  of  the  zona 
fasciculata,  here  and  there  mononuclear  makrophages  are  visible,  not 
unlike  the  phagocytic  cells  of  Kupffer  in  the  liver.  It  is  possible  to 
make  out,  too,  that  a  few  of  the  true  adrenal  cells  in  places  contain 
within  them  malarial  pigment  and  infected  corpuscles — a  fact  which 
should  not  surprise  us  when  we  consider  the  close  relation  of  certain 
parts  of  the  adrenal  parenchyma  to  the  veins  which  has  been  recently 
demonstrated  by  Manasse. 

In  places  there  are  capillary  thrombi  of  pure  streptococci,  and  cocci 
in  single  chains  or  in  clumps  are  irregularly  distributed  in  the  capil- 
lary districts.  Here  and  there  in  sections  stained  in  methylene  blue 
they  are  visible  inside  of  cells  (leucocytes,  makrophages,  endothelium 
of  capillaries). 

Many  of  the  adrenal  cells,  often  in  foci,  are  swollen,  vacuolated, 
and  fatty,  and  show  fragmented  nuclei.  The  chromatolytic  changes 
are  best  seen  in  sections  stained  in  aqueous  magenta. 

The  Lungs. — The  pulmonary  and  pleural  veins  are  widely  dis- 
tended, and  in  them  enormous  numbers  of  malarial  organisms  are 
visible.  The  parasites  are  chiefly  in  red  blood  corpuscles,  but  many 
of  them  have  been  included,  often  along  with  strejDtococci,  by  white 
cells  (chiefly  mononuclear,  but  also  polynuclear).  The  white  cor- 
puscles tend  to  accumulate  in  groups,  and  they,  together  with  infected 
red  corpuscles,  makrophages,  free  malarial  parasites,  and  masses 
of  streptococci,  are  frequently  massed  near  the  walls  of  the  vessels. 
The  parasites  are  present,  too,  in  considerable  numbers  in  the 
pulmonary  capillaries  and  in  branches  of  the  pulmonary  artery. 
Lesions  associated  with  coal  pigmentation,  and  moderate  emphy- 
sema are  present,  otherwise  the  lungs  show  no  marked  alterations. 
No  other  tissues  from  this  case  were  preserved  for  microscopic 
examination. 

The  fact  that  the  malarial  infection  was  not  recognized  during  life, 
the  enormous  number  of  parasites,  the  extensive  phagocytic  processes, 


46  Lewellys  F.  Barlcer. 

and  particularly  the  mixed  infection  and  the  lesions  in  the  kidneys 
make  this  case  one  of  more  than  ordinary  interest. 

It  may  not  be  out  of  place  here  to  make  a  few  general  remarks 
concerning  the  bacterial  infections  and  protozoan  invasions  which  may 
be  concurrent  with  malaria. 

In  the  clinical  section  of  this  fasciculus  (Report  by  Thayer  and 
Hewetson)  the  accurrence  of  multiple  malarial  infections  is  considered, 
and  the  fact  that  an  individual  may  be  infected  at  the  same  time  with 
different  groups  or  generations  of  the  same  organism  or  of  organisms 
of  different  types,  is  found  to  account  for  many  of  the  manifold  mani- 
festations of  the  disease  which  may  be  met  with.  But  in  addition  to 
a  knowledge  of  such  multiple  malarial  infections,  a  consideration  of 
the  possibility  of  the  co-existence  with  malaria  of  other  protozoan 
infections,  and  of  certain  bacterial  diseases,  both  local  and  general, 
throws  some  light  upon  certain  problems  connected  with  malaria  which 
have  been  heretofore  obscure. 

Concerning  protozoan  infections  concurrent  with  malaria  little  is 
known.  In  the  Johns  Hopkins  Hospital  one  case  of  malaria  has  been 
met  with  in  which  there  was  an  associated  dysentery  due  to  the 
amoeba  coli. 

The  bacterial  infections  which  may  be  associated  with  malaria  are 
numerous.  In  the  first  place  the  occurrence  of  a  complicating  pneu- 
monia in  malaria,  which  led  years  ago  to  so  much  polemical  literature, 
is  now  satisfactorily  explained.  The  pneumonias  which  were  be- 
lieved to  be  due  to  a  malarial  poison  are  now  known  to  be  due  not 
to  this  cause,  but  to  an  associated  bacterial  infection.  Manson  and 
others  have  described  forms  of  pneumonia  peculiar  to  the  disease 
when  occurring  in  conjunction  with  malaria,  and  it  was  believed  that 
this  pneumonia  was  particularly  prone  to  terminate  fatally.  The 
review  of  the  whole  subject  by  W.  T.  Howard  in  1859  had  an  im- 
portant influence,  and  still  merits  careful  reading.  Osier  opposed  the 
view  that  the  pneumonia  in  malaria  was  special  to  the  latter  disease. 
Finally  Bignami,  Marchiafava  and  Guarnieri  have  described  cases 
which  came  to  autopsy,  at  which  careful  bacteriological  examinations 
were  made,  by  which  it  was  proved  that  the  croupous  pneumonias  of 
malaria,  like  other  cases  of  croupous  pneumonia,  are  due  to  infection 
with  the  micrococcus  lanceolatus. 


A  Study  of  Some  Fatal  Cases  of  3Ialana.  47 

In  addition  to  croupous  pneumonia,  bronchitis  and  broncho-pneu- 
monia are  frequent  complications  of  malaria,  and  probably  may  be 
due  to  any  one  of  the  pyogenic  organisms.  The  much  disputed  typho- 
malarial  fever,  by  the  light  of  our  present  knowledge,  presents  no 
difficulties.  It  is  now  well  established  that  the  majority  of  cases  of 
so-called  typho-malarial  fever  and  typho-intermittent  fever  are  really 
genuine  cases  of  typhoid  fever.  That  a  typhoid  infection  may  co-exist 
with  an  invasion  by  the  malarial  parasites  is  indeed  certain ;  upon 
this  point  the  cases  reported  by  Osier  and  by  Gilman  Thompson  have 
left  no  room  for  doubt. 

The  rare  cases  in  which  an  acute  ulcerative  endocarditis  is  seen  in 
conjunction  with  malaria,  now  that  the  etiology  of  the  endocarditides 
is  better  understood,  will  probably  turn  out  to  be  examples  of  mixed 
bacterial  and  malarial  infection. 

Erysipelas  sometimes  co-exists  with  malaria ;  at  least  one  such  case 
has  been  met  with  in  the  wards  of  this  hospital. 

Of  the  predisposition  to  dysentery  depending  upon  alterations  in 
the  nutrition  of  the  mucous  membrane  lining  the  alimentary  canal  we 
have  already  spoken.  The  chances  of  bacterial  ingress  and  the  possi- 
bilities of  a  general  septic  infection  in  such  cases  is  obvious.  Cases  of 
general  streptococcus  infection,  such  as  the  one  described  under  the 
head  of  Case  D,  are  undoubtedly  rare. 

VI. 

ON  THE  UNEQUAL  DISTRIBUTION  OF  THE  PARA- 
SITES IN  THE  BODY  IN  MALARIAL 
INFECTION. 

The  recognition  of  the  existence  of  pigment  in  the  blood  and 
in  the  various  internal  organs  of  patients  suffering  from  malarial 
infection  antedated  by  many  years  the  discovery  of  the  organisms  of 
malaria  by  Laveran  in  1880.  But  the  studies  of  these  earlier  observers 
went  beyond  the  recognition  of  its  mere  existence,  since  it  was  noted 
by  quite  a  number  of  them  that  the  pigment  was  not  equally  dis- 
tributed throughout  the  body.  Thus,  in  the  well  known  case  of 
Meckel  in  an  insane  patient,  in  whom  the  spleen  was  enlarged  and 
deeply  pigmented,  particles  of  pigment  were  found  in  various  parts 


48  Lewellys  F.  Barker. 

of  the  body,  and  it  was  suggested  that  these  had  been  swept  out  of 
the  spleen  by  the  blood  and  carried  by  the  current  to  the  other  organs. 

Virchow  in  1848,  in  describing  the  melanaemia  of  a  malarial 
patient,  speaks  of  the  large  accumulation  of  pigment  in  the  spleen 
and  liver,  and  at  the  same  time  notes  the  finding  of  this  substance 
enclosed  in  the  cells  in  the  blood  of  the  heart. 

Planer  suggested  that  the  comatose  and  apoplectic  forms  of  severe 
malaria  might  be  explained  by  the  lodgment  of  emboli  of  pigment  in 
the  brain  capillaries.  Frerichs  attributed  the  atrophy  of  the  paren- 
chyma of  the  liver,  observed  in  some  of  the  cases,  to  obstruction  in 
the  liver  capillaries. 

Since  the  discovery  of  the  malarial  parasite,  those  who  have  had 
opportunities  of  studying  specimens  of  the  fresh  blood  from  a  large 
number  of  cases  of  malarial  infection,  have  not  only  been  able  to 
recognize  certain  distinct  types  of  parasites  as  belonging  to  the  various 
clinical  forms  of  the  disease,  but  have  also  been  able  to  add  some 
curious  facts  relative  to  the  distribution  of  the  organisms  in  the  blood 
and  organs.  Councilman,  Celli  and  Marchiafava  and  others  observed 
in  cases  of  the  comatose  form  of  pernicious  malaria,  the  frequent  oc- 
currence in  the  brain  of  capillaries  plugged  with  parasites.  Council- 
man, too,  early  pointed  out  that  the  number  of  crescentic  forms  of 
the  organism  in  the  circulating  blood  was  seldom  large,  but  that 
their  tendency  was  to  accumulate  in  considerable  numbers  in  the  spleen. 

The  question  of  the  unequal  distribution  of  the  parasites  in  the 
body  assumes  especial  importance  when  considered  in  connection  with 
the  three  main  types  of  the  malarial  organisms.  Without  entering 
into  a  detailed  description  of  the  individual  observations  which  have 
led  up  to  our  knowledge  of  the  subject  as  it  may  at  present  be 
formulated,  the  broad  statement  may  be  made  that  in  infections  with 
quartan  parasites  one  sees  the  most  equal  distribution  of  the  parasites 
throughout  the  blood  and  various  organs,  and  that  in  infections  with 
parasites  of  the  aestivo-autumnal  variety  the  most  unequal  distribution 
is  encountered.  In  infection  with  parasites  of  the  tertian  type,  the 
character  of  the  distribution  may  be  said  to  stand  between  that  of 
the  quartan  and  that  of  the  aestivo-autumnal  infections,  approaching 
perhaps  a  little  more  closely  to  the  former. 

In  the  quartan  fevers  the  parasites  are  nearly  always  to  be  seen  in 
numbers  in  the  blood  in  any  of  the  peripheral  parts,  and  during  the 


A  Study  of  Some  Fatal  Cases  of  Malaria.  49 

paroxysm  many  segmenting  bodies,  although  they  show  a  decided 
tendency  to  accumulate  in  the  organs,  are  observable  in  the  blood 
taken  from  the  finger-tip  or  from  the  lobule  of  the  ear.  Indeed,  so 
regular  is  the  distribution  of  the  organisms  throughout  the  body  in  this 
type  of  malarial  fever,  that  a  tolerably  definite  estimate  of  the  severity 
of  the  infection  can  be  made  simply  from  the  number  of  organisms 
to  be  seen  in  the  fresh  blood  slide. 

The  parasites  in  tertian  fever,  although  usually  quite  abundant  in 
the  circulating  blood,  show  decidedly  a  more  marked  tendency  to 
accumulate  in  the  internal  organs,  such  as  the  spleen,  the  liver,  and  the 
marrow  of  the  bones.  This  is  notably  true  at  the  time  of  the  par- 
oxysms when  the  segmenting  organisms,  although  usually  still  present 
in  severe  infections  in  considerable  numbers  in  the  peripheral  blood, 
are  for  the  most  part  retained  in  the  internal  organs  and  especially 

in  the  spleen. 

But  it  is  in  the  infections  with  the  aestivo-autumnal  parasites,  in- 
fections which  include  the  majority  of  comatose  and  other  pernicious 
cases,  that  the  most  curious  and  marked  variations  in  the  distribution 
of  the  parasites  are  to  be  met  with,  and  the  findings  in  these  cases 
have  gone  far  to  make  clear  the  diverse  and  startling  clinical  mani- 
festations to  which  these  infections  may  give  rise.  It  is  in  these 
cases  more  particularly  that  pathologists,  through  observations  at  post- 
mortem examinations,  have  been  able  to  make  important  contributions 
to  the  understanding  of  a  disease,  the  main  progress  in  which  is  un- 
doubtedly due  to  the  work  of  the  clinical  investigators. 

In  the  aestivo-autumnal  infections,  the  number  of  organisms  in 
the  blood  circulating  in  the  peripheral  parts  afford  as  a  rule  very 
insufficient  data  upon  which  to  base  an  idea  of  the  severity  of  the 
infection.  As  clinical  experience  has  taught,  numerous  slides  pre- 
pared from  the  peripheral  blood  may  show  very  few  organisms,  and 
these  often  of  the  type  most  difficult  to  recognize,  while  in  a  drop  of 
blood  taken  from  the  spleen  quite  a  large  number  of  the  parasites 
may  often  be  made  out  with  ease. 

The  occurrence  of  segmenting  organisms  in  the  peripheral  blood  is 
a  phenomenon  of  extreme  rarity  in  aestivo-autumnal  infections. 

Golgi,  Bignami  and  others  have  pointed  out  the  fact,  which  can 
easily  be  substantiated  by  careful  observation,  that  in  aestivo-autumnal 
malaria  the  distribution  of  the  parasites  may  vary  in  different  parts 


50  Lewellys  F.  Barker. 

of  the  same  organ.  Thus  in  the  fluid  obtained  from  tapping  the 
spleen  in  different  regions,  the  number  of  organisms  is  prone  to  vary 
considerably,  and  in  sections  of  the  spleen,  liver,  and  other  organs, 
it  is  not  difficult  to  convince  one's  self  of  the  disparity  in  the  number 
of  organisms  in  different  vascular  territories. 

Among  the  most  interesting  and  most  important  of  the  local  accu- 
mulations of  the  parasites  is  the  formation  of  parasitic  thrombi.  In 
the  comatose  forms  of  malarial  fever  it  is  not  uncommon  to  find 
capillaries  and  small  veins  in  the  brain  distended  with  masses  of 
malarial  parasites  of  the  aestivo-autumnal  variety,  which  probably 
are  identical  with  the  so-called  pigment  thrombi  of  the  early  observers. 
These  may  be  pigmented  organisms  and  segmenting  forms,  or  accord- 
ing to  Bignami,  the  thrombi  may  sometimes  be  made  up  of  the  small 
pale  non-pigmented  bodies  first  described  by  Marchiafava  and  Celli. 

The  profound  disturbances  of  nutrition  necessarily  consequent  upon 
such  a  condition,  which  is  not  unfrequently  accompanied  by  necrosis, 
would  alone,  without  a  consideration  of  the  effects  of  the  toxines  which 
the  parasites  produce,  suffice  to  explain  many  of  the  clinical  phenomena 
referable  to  intra-cranial  involvement. 

It  is  not  to  be  supposed  that  in  any  given  case,  all  the  capillaries 
are  alike  affected.  As  a  matter  of  fact,  while  two  or  three  may  be 
completely  filled  with  parasites,  their  neighbors  for  some  distance 
around  may  be  almost  or  entirely  free  from  them.  When  we  consider 
the  many  variations  possible  in  the  implication  of  the  capillaries  in  any 
organ,  the  diversity  of  the  disturbances  of  the  cerebral  functions 
observable  clinically  becomes  easily  understandable.  It  is  not  difficult 
to  conceive  that  herein  may  lie  the  key  to  the  transitory  aphasias,  the 
variation  in  degree  extent  or  duration  of  the  paralyses,  or  of  the 
mental  irregularities  occasionally  noticeable  in  the  severer  forms  of 
aestivo-autumnal  fever;  and  when,  along  with  other  things,  we 
remember  that  comparatively  limited  disturbances  of  the  circulation 
in  certain  of  the  vital  centres,  such  as  the  medulla,^  suffice  at  times 
to  cause  sudden  death,  it  is  not  surprising  that  the  type  of  malarial 
infection  which  is  associated  with  the  possible  occurrence  of  the 
capillary  thrombi  of  parasites  should  have  won  for  itself  the  title 
of  malaria  pernidosa. 

^  Marchiafava  has  recorded  a  case  in  which  he  noticed  a  special  localization  of  the 
parasites  in  the  neighborhood  of  the  bulbar  nuclei. 


A  Study  of  Some  Fated  Cases  of  Malaria.  51 

In  describing  the  findings  in  Case  B,  attention  was  directed  to 
the  accumulations  of  parasites  within  the  capillaries  and  small  veins 
of  the  mucous  membrane  of  the  stomach,  and  to  the  necroses  on  the 
surface  of  the  mucosa,  which  could  fairly  be  attributed  to  the  dis- 
turbances in  the  nutrition  of  the  part.  There  are  numerous  instances 
in  the  literature  in  which,  after  death,  a  similar  condition  has  been 
found  in  the  vessels  of  the  mucous  membrane  of  the  intestines,  the 
patient  during  life  having  shown  the  symptoms  of  profound  intestinal 
disturbance  and  even  of  an  acute  dysentery.  The  cases  are  so  charac- 
teristic as  to  be  worthy  of  a  definite  place  in  nosology  and  the  names 
malaria  perniaiosa  cholerica,  and  malaria  pernioiosa  algida  have  been 
suggested  to  describe  these  forms. 

It  would  probably  be  fair,  arguing  by  analogy,  to  assume — and 
many  observations  would  seem  to  confirm  the  view — that  the  occur- 
rence of  similar  parasitic  thrombi  in  other  organs  of  the  body  may 
lead  to  alterations  in  nutrition  and  function  which  materially  influence 
the  course  and  progress  of  the  disease. 

Any  attempt  to  explain  the  reasons  for  this  unequal  distribution  is 
beset  with  many  difficulties.  While  the  slow  circulation  and  the 
calibre  of  the  vessels  in  certain  organs  certainly  play  a  part,  yet  the 
distribution  of  parasites  in  all  forms  of  malaria  is,  as  we  have  seen, 
very  different  from  that  of  inert  substances  when  introduced  into  the 
circulating  blood.  Undoubtedly,  many  factors  have  to  be  considered, 
and  how  far  any  one  or  more  are  concerned  in  a  given  case  is  difficult 
to  determine. 

In  another  section,  in  which  phagocytosis  is  dealt  with,  the  locali- 
zation of  the  parasites  in  certain  organs  inside  of  cells  will  be  more 
fully  commented  upon.  As  Bignami  suggests,  the  activity  or  in- 
activity of  the  phagocytes  of  a  certain  organ  may  have  an  important 
influence  upon  the  distribution.  He  lays  stress,  too,  upon  the  fact 
that  the  parasites  are  usually  endoglobular,  and  that  infected  red 
corpuscles,  from  loss  of  elasticity  or  other  physical  alteration,  may  be 
impeded  in  their  progress  and  tend  to  accumulate  in  the  viscera  in 
which  the  circulation  is  slowed.  It  is  certainly  true  that  in  the 
abdominal  area  where  the  slowness  of  the  circulation  is  accentuated 
in  malaria,  owing  to  obstruction  in  the  liver  by  endothelial  swelling 
or  accumulation  of  makrophages  within  the  capillaries,  the  massing 
of  the  parasites  is  ordinarily  marked,  while  in  organs  in  which  the 
4 


52  Lewellys  F.  Barker, 

circulation  is  most  active,  very  few  parasites  as  a  rule  are  present. 
That  the  parasites  and  infected  red  cells  collect  along  with  the  white 
corpuscles  on  the  inner  walls  of  the  larger  veins  is  a  fact  which  could 
be  confirmed  in  many  of  the  specimens  from  the  autopsies  of  this  re- 
port, but  as  to  the  explanation  of  this  phenomenon  nothing  is  as  yet 
certainly  known. 

As  regards  the  tendency  in  the  pernicious  cases  to  the  formation 
of  thrombi  composed  of  parasites  in  certain  vascular  territories  our 
knowledge  is  most  at  fault.  The  idea  that  certain  capillaries  become 
plugged  with  makrophages,  and  that  in  the  dilated  vessel  behind  the 
point  of  obstruction  the  corpuscles  in  the  stagnant  blood  all  become 
infected,  will  not  suffice  for  the  explanation  of  all  the  instances. 
That  vaso-motor  influences  in  certain  vascular  areas  play,  as  Bignami 
suggests,  an  important  r6le  seems  plausible,  especially  in  cases  of  the 
pernicious  algid  form. 

It  is  perhaps  not  impossible  to  learn  something  from  the  analogies 
observable  in  tumor  metastases,  in  bacterial  infections  or  even  in  simple 
intoxications.  It  has  long  been  a  puzzle  to  pathologists  why  in  cases 
of  general  sarcomatosis  or  carcinosis,  where  the  distribution  is  through 
the  general  circulating  blood,  that  in  some  cases  one  organ  or  set  of 
organs,  in  other  cases  other  portions  of  the  viscera  have  remained 
free  or  nearly  free  from  metastatic  growths. 

Again  as  regards  the  general  bacterial  infections  those  who  have  as 
a  matter  of  routine  made  bacteriological  investigations  of  all  the 
organs  at  a  number  of  autopsies,  will  be  familiar  with  the  fact  that 
in  such  cases  the  bacteria  even  at  perfectly  fresh  autopsies  are  by  no 
means  equally  apportioned  through  the  blood  and  viscera.  Indeed, 
it  is  a  common  occurrence  to  find  that  one  or  two  of  the  organs  contain 
relatively  many  fewer  bacteria  than  the  others.  But  that  there  is 
little  regularity  in  the  inequality  of  distribution  is  shown  by  the  study 
of  numerous  cases  of  general  infection  with  the  same  micro-organism, 
e.  g.  the  streptococcus.  Whereas  the  plate  cultures  made  from  the 
spleen  in  one  case  of  septicaemia  may  be  closely  crowded  with  colonies 
and  those  from  the  liver  contain  only  a  few,  in  another  instance  the 
conditions  may  be  exactly  the  reverse.  Every  one  is  acquainted  with 
the  relative  immunity  of  some  organs  in  acute  general  miliary  tuber- 
culosis, an  immunity  which  can  be  made  out  often  from  the  naked 
eye  appearances  alone,  although  it  is  often  difficult  to  decide  whether 


A  Study  of  Some  Fatal  Cases  of  Malaria.        ^  53 

the  irregularity  is  an  expression  of  a  primary  inequality  of  distribution, 
or  to  differences  in  the  resistance  offered  to  the  local  multiplication  of 
the  distributed  organisms  or  again  to  the  different  effect  which  they 
produce  on  the  tissues  in  which  they  develop. 

And  after  all  when  we  consider  the  fact  that  in  malaria  we  have  to 
deal  with  a  crude  mixture  of  malarial  parasites,  blood  corpuscles  and 
blood  plasma,  the  anomalous  distribution  of  the  parasites,  as  ascer- 
tained by  post-mortem  examinations,  should  be  much  less  difficult  to 
account  for  than  the  unequal  diffusion  through  the  organs  of  sub- 
stances which  are  dissolved  in  the  blood,  a  phenomenon  which  of  late 
has  attracted  considerable  attention.  It  is  scarcely  necessary  to  call  to 
mind  that  normally  certain  chemical  bodies  are  removed  from  the 
circulating  fluid  by  various  glands  to  serve  in  the  manufacture  of 
secretions.  Again,  the  discovery  of  the  accumulation  of  poisons  in 
certain  organs,  e.  g.,  morphine  in  the  liver,  spleen  and  bone  marrow, 
and  certain  other  vegetable  poisons  in  the  liver,  for  purposes  of  elimi- 
nation or  neutralization  must  be  reckoned  among  the  observations 
which  help  to  make  general  toxicology  interesting.  In  the  domain 
of  bacterial  toxicology,  Welch  and  Flexner  have  demonstrated  the 
occurrence  of  definite  focal  lesions  in  the  tissues  of  the  body  produced 
by  a  soluble  poison  circulating  in  the  blood,  a  finding  which  is  scarcely 
compatible  with  any  assumption  other  than  that  the  dissolved  poisons 
are  not  evenly  distributed  even  in  the  individual  organs. 

Now  that  the  vital  characteristics  and  varying  sensibilities  of  uni- 
cellular organisms  are  becoming  better  known  and  appreciated,  we 
have  learned  to  have  more  respect  for  a  cell  as  an  individual,  and  the 
conclusion  that  this  unequal  distribution  is  dependent  upon  a  com- 
plexity of  factors  will  not  excite  surprise.  If  it  be  borne  in  mind 
that  the  parasites  are  constantly  exercising  their  metabolic  functions ; 
if  the  question  of  food  relations  and  that  of  the  influence  of  excre- 
tory substances  from  the  parasites  together  with  the  alterations  in  the 
metabolism  of  the  cells  of  the  various  tissues  (e.  g.,  those  dependent 
upon  the  destruction  of  red  corpuscles)  be  taken  into  account,  it  will  be 
seen  that  the  whole  problem  of  anomalous  distribution,  as  influenced 
by  factors  incident  to  the  parasite  and  factors  incident  to  the  cells, 
may  become  extremely  complicated,  and  that  we  can  scarcely  hope  in 
the  very  near  future  that  all  the  intricacies,  whether  they  be  due 
simply  to  mechanical  factors  or  to  those  which  we  must  regard  as  the 
outcome  of  vital  influences,  will  be  explained. 


54  ,  Lewellys  F.  Barker. 

VII. 
ON  PHAGOCYTOSIS  IN  MALARIA. 

Among  those  who  have  insisted  upon  the  importance  of  the  part 
played  in  raalaHa  by  the  so-called  phagocytes  are  Metschnikoff, 
Guarnieri,  Bignami,  Laveran,  Dock,  and  especially  Golgi  and  Basti- 
anelli.  As  has  been  said  above,  a  study  of  the  literature  shows  that 
malarial  pigment  had  been  observed  in  the  cells  of  the  different  organs 
and  in  the  white  cells  floating  in  the  blood  long  before  the  parasitic 
nature  of  the  disease  had  been  established,  and  a  great  deal  of  this 
pigment  is  now  known  to  be  within  the  bodies  of  the  parasites. 

The  inclusion  of  the  malarial  pigment  and  of  the  malarial  parasites 
within  white  cells,  fixed  or  floating,  occurs  in  all  cases  of  malaria, 
although  the  extent  of  the  process  varies  somewhat  in  different  in- 
dividuals, and  with  the  different  varieties  of  malarial  infection.  The 
microscopic  examination  of  the  cases  which  came  to  autopsy  here, 
showed  that  the  reports  of  other  observers  on  this  subject  had  not 
been  exaggerated. 

The  cells  actively  concerned  in  phagocytosis  are  not  all  of  one  kind. 
Besides  different  varieties  of  leucocytes,  certain  of  the  fixed  cells  of 
the  organs,  the  endothelial  cells  generally,  but  especially  those  in  the 
liver  and  spleen,  the  cells  of  Kuppfer  in  the  former,  and  the  cells  of 
the  pulp-cords  in  the  latter,  take  no  unimportant  part  in  the  process. 

The  contents  of  these  different  phagocytic  cells  vary  also.  Speaking 
generally,  it  may  be  stated  that  the  cells  concerned  may  enclose  within 
their  bodies  any  of  the  following :  (1)  red  blood  corpuscles,  many  of 
them  altered,  others  apparently  little  changed ;  (2)  fragments  of  red 
corpuscles ;  (3)  masses  of  haemosiderin  (probably  formed  within  the 
cells) ;  (4)  malarial  parasites,  in  different  phases  of  the  developmental 
cycle,  many  of  them  endoglobular,  many  of  them  degenerated  or  going 
to  pieces  ;  (5)  malarial  pigment,  especially  the  central  pigment  clumps 
from  segmenting  parasites ;  and  (6)  white  cells  both  mononuclear  and 
polynuclear.  A  phagocytic  cell  is  sometimes  seen  to  contain  all  of 
these  structures  at  one  time,  but  this  is  not  a  common  observation. 
Special  names  have  been  assigned  to  the  phagocytic  cells  in  accordance 


A  Study  of  Some  Fatal  Cases  of  Malaria.  55 

with  the  character  of  their  contents — thus  the  leucocytes  containing 
malarial  pigment  are  spoken  of  as  "  pigment! ferous  "  or  "  melani- 
ferous  ; "  the  cells  containing  red  corpuscles  as  "  globuliferous ; " 
while  those  containing  parasites  are  known  as  "  amoebiferous  "  cells. 
Following  this  nomenclature  the  cells  containing  other  phagocytes 
might  be  called  "  phagocytiferous,"  just  as  those  containing  white 
corpuscles  have  been  spoken  of  as  "  leucocytiferous/'  but  it  is  doubtful 
if  much  is  to  be  gained  by  any  extension  of  this  awkward  terminology. 
The  different  forms  of  phagocytes  seen  in  our  cases  have  been  fully 
described  in  the  protocols  of  the  microscopic  examinations,  and  need 
not  be  further  considered  here.  One  point  to  which  attention  may 
perhaps  be  directed  is  the  manifest  division  of  labor  which  exists 
among  the  various  forms  of  phagocytic  cells.  While  any  one  of  the 
varieties  seemed  capable  of  taking  up  at  times  almost  any  of  the 
substances  above  mentioned,  yet  when  the  tissues  are  studied  care- 
fully it  is  easy  to  make  out  that  they  do  not  all  contain  these  various 
substances  in  the  same  proportions,  but  that  as  a  matter  of  fact  the 
white  corpuscles  and  endothelial  cells  appear  to  possess  more  or 
less  definite  elective  affinities.  For  example,  in  Case  T>  while  the 
mononuclear  leucocytes  contained  the  majority  of  well  preserved 
parasites,  the  polynuclear  leucocytes  showed  a  preponderance  of  the 
segmental  pigment ;  while  the  makrophages  in  the  spleen  and  liver 
contained  large  numbers  of  infected  and  otherwise  altered  red  cor- 
puscles and  remains  of  malarial  parasites,  the  endothelial  cells  of  the 
spleen  and  liver  often  contained  blood  pigment  to  the  exclusion  of  all 
other  visible  kinds  of  foreign  material.  Laveran,  Councilman,  and 
Golgi  early  noted  that  leucocytes  carrying  pigment  were  most  abundant 
in  the  blood  just  after  the  onset  of  a  paroxysm,  and  suggested  that 
the  increased  number  of  pigmented  corpuscles  might  depend  upon 
the  setting  free  of  large  quantities  of  pigment  during  segmentation. 
Supposing  that  there  might  exist  a  periodicity  to  the  phagocytosis 
corresponding  more  or  less  nearly  to  the  developmental  cycle  of  the 
parasite,  Golgi  made  certain  studies,  the  result  of  which  convinced 
him  that  the  idea  had  a  basis  in  fact.  From  these  investigations  he 
concluded  that  the  white  cells  in  the  organs,  particularly  in  the  spleen, 
played  even  a  more  active  part  in  phagocytosis  than  those  in  the 
blood,  a  conclusion  which  had  also  been  reached  by  Metschnikoff 
from  the  study  of  sections  of  the  spleen  and  liver  in  malaria.     Basti- 


56  Lewellys  F.  Barker. 

anelli  found  further  in  his  extensive  study  of  the  leucocytes  in  malaria 
a  marked  increase  in  the  number  of  pigmented  leucocytes  in  certain 
cases  at  the  beginning  of  the  febrile  paroxysm,  but  as  might  have 
been  expected  saw  less  evidence  of  periodicity  in  the  aestivo-autumnal 
cases.  He  seems  inclined  to  attribute  the  major  share  of  the  phago- 
cytic work  to  the  large  mononuclear  elements.  The  same  writer 
confirmed  the  observations  of  Bignami  concerning  the  degeneration 
of  phagocytic  leucocytes  and  suggests  that  the  diminution  in  the 
number  of  leucocytes  in  malaria  may  be  attributed  to  this  cause. 
John  S.  Billings,  Jr.,  who  made  accurate  counts  of  the  total  number 
of  leucocytes,  and  also  differential  counts  of  the  various  forms  of  white 
corpuscles  by  Ehrlich's  methods  of  color  analysis,  before,  during  and 
after  the  paroxysms,  found  that  in  certain  cases  there  was  always  a 
diminution  in  the  number  of  leucocytes  during  the  febrile  paroxysm. 
In  a  chart  accompanying  his '  article  in  which  a  composite  curve  of 
the  temperature  is  compared  with  a  similar  one  representing  the 
number  of  white  corpuscles,  it  is  evident  that,  while  just  before  the 
chill  the  number  of  white  cells  to  the  cubic  millimetre  is  approxi- 
mately normal,  there  is  a  steady  though  not  very  marked  increase  in 
the  number  for  from  two  to  three  hours  until  a  maximum  is  reached, 
after  which  there  is  a  relatively  sharp  and  steady  decline  correspond- 
ing with  the  fall  in  temperature  until  a  minimum  is  reached  which  is 
considerably  below  the  normal.  As  to  the  color  analysis  of  the  leuco- 
cytes, Bastianelli  found  a  decrease  in  the  leucocytes  with  polymorphous 
nuclei  with  an  increase  in  the  large  and  small  mononuclear  elements. 
According  to  Billings  a  decrease  in  the  polynuclear  and  an  increase 
in  the  large  mononuclear  cells  is  constant,  while  there  is  no  regularity 
as  to  the  percentage  of  small  mononuclears  and  eosinophiles. 

The  clinical  observations  just  referred  to  are  of  considerable  interest 
in  connection  with  the  appearances  in  the  organs  at  autopsy,  and  it  is 
interesting  too  to  compare  the  examples  of  phagocytosis  observable 
in  the  blood  drawn  from  the  circulation  during  life  (vide  a  report  by 
Thayer  and  Hewetson)  with  those  seen  in  the  sections  from  the  cases 
now  reported.  According  to  these  observers  it  is  extremely  rare  to 
notice  any  active  phagocytic  tendencies  on  the  part  of  the  mononuclear 
elements  to  parasites  in  blood  taken  from  the  finger  or  ear,  although 
it  is  by  no  means  uncommon  to  see  a  leucocyte  with  a  polymorphous 
nucleus  gradually  enclose  a  flagellating  parasite  or  a  fragmented  ex- 


A  Study  of  Some  Fatal  Cases  of  Malaria.  57 

tra-cellular  body  in  the  fresh  blood  slide.  It  will  have  been  seen 
above,  however,  that  in  the  blood  in  the  sections  from  Case  D 
the  majority  of  parasites  are  enclosed  within  large  mononuclear 
leucocytes.  It  has  been  stated,  too,  that  neither  the  parasites  nor 
the  including  cells  necessarily  show  evidences  of  degeneration.  The 
question  naturally  arises,  "Could  the  enclosing  of  the  parasites 
by  the  large  mononuclear  leucocytes  in  this  case  have  been  a  post- 
mortem phenomenon  ?  "  Dock  has  shown  that  the  malarial  parasites 
are  arrested  in  their  development  soon  after  the  death  of  the  patient, 
and  it  is  of  course  quite  conceivable,  though  in  my  opinion  it  is 
improbable,  that  certain  changes  occurring  in  the  parasites  inside 
the  body  after  death  rendered  them  suitable  to  be  taken  up  by 
the  large  white  cells.  It  is  unfortunate  that  in  this  case  no  blood 
examination  was  made  during  life.  So  many  of  the  large  mononu- 
clear leucocytes  as  seen  in  the  sections  contain  parasites  within 
their  protoplasm,  that  had  the  ingestion  occurred  ante-mortem  it  could 
scarcely  have  been  overlooked  upon  examination  of  the  fresh  blood. 

The  original  statement  of  Metschnikoflf  that  the  endothelial  cells  of 
the  capillaries,  especially  in  the  liver,  take  up  the  parasites  has  been 
questioned  by  some  observers.  The  tissues  from  the  autopsies  here 
reported  unquestionably  confirm  Metschnikoff's  statement,  though  as 
we  have  said,  the  endothelial  cells  are  much  more  prone  to  take  up 
the  remains  of  altered  blood  corpuscles  than  to  include  malarial 
pigment  or  the  parasites. 

The  red  blood-corpuscle-carrying  cells  and  the  huge  phagocytic 
cells  of  the  spleen  attract  special  attention.  When  one  studies  sections 
of  the  spleen  and  sees  the  enormous  number  of  these  makrophages, 
the  accumulations  of  fragmented  red  corpuscles,  the  necroses,  and  the 
dilatation  of  the  blood-vessels  in  this  organ,  he  has  not  to  go  far  to 
seek  an  explanation  for  its  enlargement  in  malarial  infection.  The 
number  of  makrophages  which  are  carried  from  the  spleen  through 
the  splenic  vein  into  the  liver  cannot  fail  to  be  of  considerable  signi- 
ficance. As  was  pointed  out  in  the  description  of  the  tissues  they 
frequently  appear  to  occlude  the  liver  capillaries,  and  to  offer  a  serious 
impediment  to  the  onflow  of  blood.  Guarnieri  thought  that  this 
obstruction  in  the  liver  capillaries  might  account,  in  part  at  least,  for 
the  enlargement  of  the  spleen  (venous  stasis),  and  suggested  that 
possibly  the  pernicious  forms  of  malaria  might  depend  upon  an  in- 


58  Lewellys  F.  Barker. 

toxication  due  to  the  disturbance  of  the  functions  of  the  liver — a 
view  which  he  has  doubtless  given  up  long  before  now. 

The  question  may  fairly  be  asked,  "What  becomes  of  these  migrated 
spleen  cells  loaded  down  with  ingested  material?"  If  we  can  judge 
by  an  examination  of  the  tissues  elsewhere,  there  are  comparatively  few 
carried  through  the  liver  into  the  general  circulation,  unless  indeed 
the  greater  number  of  them  have  been  diminished  in  size,  and  have 
gotten  rid  of  sodae  of  their  contents  so  that  they  were  able  to  pass 
through.  This  they  could  do  in  part  through  cellular  digestion.  It 
seems  to  me,  however,  that,  carrying  as  they  do,  besides  malarial 
parasites  and  malarial  pigment,  considerable  quantities  of  haemoglobin 
and  of  blood  coloring  matter  already  altered  within  the  cell  so  as  to 
give  the  blue  iron  reaction,  these  cells  may  exercise  an  important 
function  in  carrying  to  the  liver  the  materials  for  the  manufacture  of 
bile.  It  is  not  inconceivable  that  these  makrophages  lying  in  direct 
contact  with  the  endothelium  of  the  hepatic  capillaries  could  yield  up 
a  portion  or  all  of  their  contents  to  the  latter.  It  would  indeed  be 
interesting  if  it  should  turn  out  that  the  blood  pigment  in  the  makro- 
phages, in  the  vascular  endothelium,  and  in  Kupffer's  cells  stood  in 
some  such  direct  relation  to  the  bile  manufactured  by  the  liver  cells. 
Certainly  the  liver  cells  must  draw  their  iron  substances  from  the 
blood,  and  from  what  we  know  now-a-days  of  the  varied  capacities 
of  white  blood  corpuscles  and  of  endothelial  cells,  the  occurrence  of 
some  such  interchange  of  raw  materials  as  has  been  hinted  at  would 
not  be  surprising.  It  may  be  that  the  study  of  pathological  accentu- 
ation of  the  bile-making  activities  of  the  liver  may  throw  light  in  the 
future  on  the  still  obscure  physiological  processes  which  go  on  in 
this  organ  .^  The  metabolic  processes  of  the  body  tend  towards  eco- 
nomy ;  the  re-making  of  materials  by  diflPerent  organs  is  common, 
the  refuse  from  one  organ  often  being  essential  for  the  nutrition  and 
well  being  of  certain  of  the  others  (law  of  Treviranus) ;  and  this  being 
so,  the  relations  of  phagocytosis  to  the  nutritional  activities  of  the 
body  form  an  interesting  topic  for  investigation. 

The  makrophages  in  the  vessels  of  the  mucous  membrane  of  the 
alimentary  tract  have  been  mentioned  in  connection  with  Case  A. 
Dock  describes  finding  one  similar  cell  in  one  of  his  cases.     It  is 

^  Compare  the  researches  of  Dr.  William  Hunter,  On  the  Physiology  and  Pathology 
of  Blood  Destruction,  Brit.  Med.  Jour.,  1892,  ii,  p.  1159  and  1223. 


A  Study  of  Some  Fatal  Cases  of  Malaria.  59 

generally  stated  that  eosinophilic  cells  never  act  as  phagocytes  in 
malaria.  The  late  Dr.  Oppenheimer,  however,  recently  showed  me 
in  a  slide  of  fresh  blood  a  makrophage  which  contained  large,  round, 
yellowish,  refractive  granules  which  closely  resembled  the  ordinary 
eosinophilic  granulation  ;  the  cell  enclosed  several  infected  corpuscles. 

It  is  not  improbable  that  the  active  process  of  phagocytosis,  aside 
from  the  mechanical  obstruction  which  the  cells  may  cause,  helps  to 
determine  the  irregular  distribution  of  the  parasites  in  the  body.  At 
any  rate  it  is  certain  that  the  parasite?  tend  to  accumulate  in  ordinary 
cases  in  the  spleen  and  liver,  the  sites  where  the  phagocytosis  is  most 
active.  We  have  already  pointed  out,  however,  that  the  phagocytosis 
can  be  only  one  of  many  factors  which  influence  the  distribution. 

There  is  a  considerable  amount  of  literature  bearing  upon  the  re- 
lation of  phagocytosis  to  "  natural  resistance  "  and  to  "  spontaneous 
cure "  in  malaria.  It  is  a  perfectly  well  ascertained  fact  that  many 
patients  suffering  from  malaria  do,  when  placed  under  more  favorable 
hygienic  conditions,  get  entirely  well  without  the  administration  of 
quinine  or  of  any  other  drug.  It  is  by  no  means  uncommon  to  see 
patients  begin  to  improve  almost  immediately  after  being  put  to  bed 
in  a  hospital  ward,  the  paroxysms  becoming  successively  less  severe, 
and  the  organisms  gradually  disappearing  from  the  blood  until  all  have 
vanished.  What  the  natural  mechanisms  of  defense  are  which  lead  to 
spontaneous  cure,  and  which  inhibit  the  growth  and  multiplication  of 
many  parasites  even  in  the  severer  infections,  it  is  as  yet  impossible 
to  say  definitely.  All  authorities  are  agreed  that  many  of  the  progeny 
of  segmenting  organisms  are  disposed  of  at  the  end  of  each  paroxysm, 
since  did  all  the  young  ones  gain  entrance  to  red  corpuscles  and  go  on 
to  full  development,  the  blood  would  after  a  very  few  paroxysms  show 
very  few  uninfected  red  globules,  and  those  who  hold  that  the  blood 
serum  kills  off  many  of  the  small  hyaline  forms  before  they  gain 
entrance  to  the  interior  of  red  corpuscles  are  not  without  grounds  for 
their  belief.  Others  maintain  that  the  white  corpuscles,  the  endothe- 
lial cells,  and  the  spleen-pulp  cells  enclose  many  of  the  segments 
immediately,  even  before  they  have  been  deleteriously  affected  by  the 
blood  serum.  The  relative  efficiency  of  the  blood  serum  and  of  the 
phagocytes  with  relation  to  natural  resistance,  is  being  fought  out  on 
this  as  well  as  on  other  grounds.  There  can  be  little  doubt  {vide  pro- 
tocols) that  many  of  the  parasites  taken  up  by  the  phagocytic  cells  are 


60  Lewellys  F.  Barker. 

enclosed  within  red  corpuscles,  and  it  may  very  well  be  that  the 
alteration  in  the  bodies  of  the  red  corpuscles  may  help  to  determine, 
especially  in  the  spleen,  their  inclusion  by  white  cells.  That  the  re- 
reception  of  the  parasites  can  do  harm  to  the  cells  in  many  cases  would 
seem  to  be  evidenced  by  the  fact  that  many  of  the  makrophages  are 
necrotic,  their  nuclei  staining  feebly  or  not  at  all  in  basic  dyes,  and  their 
protoplasm  showing  an  increased  affinity  for  acid  dyes  like  eosin.  The 
diminution  in  the  number  of  leucocytes  after  a  paroxysm,  however,  is 
much  more  probably  due  to  the  effects  of  toxines  set  free  at  segmen- 
tation, and  if  so  would  be  quite  analogous  to  the  similar  diminution 
(leukolysis)  which  immediately  follows  the  experimental  injection  of 
bacterial  toxines  into  animals. 

The  changes  which  the  parasites  undergo  within  the  bodies  of  the 
white  cells  are  interesting  to  watch.  It  would  appear  that  sometimes 
the  parasite  ruptures  and  that  the  pigment  is  gradually  set  free  to  be 
distributed  in  more  or  less  regular  lines  throughout  the  protoplasm 
of  the  including  cell.  How  long  the  parasites  may  live  after  inclusion 
appears  doubtful.  That  they  are  taken  up  while  alive  seems  certain 
from  the  many  observations  of  skilled  investigators.  It  is  usually 
taken  for  granted  that  the  phagocyte  is  the  active  agent  and  takes  up 
the  parasites,  a  much  more  likely  view  than  that  the  parasites  enter 
the  white  cells  to  feed  on  their  deuteroplasm  (fragmented  or  degener- 
ated red  corpuscles).  It  is  not  certain,  however,  that  the  parasites 
may  not  continue  an  intra-phagocytic  existence  at  least  for  some  time, 
especially  if  the  protoplasm  of  the  phagocyte  is  degenerated.  Golgi 
has  even  gone  so  far  as  to  suggest  that  the  parasites  may  grow  and 
multiply  within  certain  of  the  body  cells.  Bignami  cannot  conceive 
of  any  explanation  for  the  so-called  "  cases  of  latent  infection  "  in 
malaria,  that  is,  those  instances  in  which  an  apparently  cured  malarial 
infection  subsequently  becomes  active,  without  the  patient  having  in 
the  meantime  been  exposed  to  re-infection  in  a  malarial  district,  except 
by  assuming  the  continuance  of  some  resistant  forms  inside  of  cells. 
Bignami  argues  that  inasmuch  as  certain  cells,  leucocytes  and  endo- 
thelial cells  for  example,  are  known  to  take  into  themselves  a  certain 
number  of  sporulating  forms,  and  further,  since  in  patients  with  a 
recently  cured  malarial  infection  who  have  died  from  some  intercurrent 
disease  certain  cells  in  the  spleen,  liver  and  bone  marrow,  retain  the 
traces  of  infection,  it  is  much  more  likely  that  the  germs  of  latent 


A  Study  of  Some  Fatal  Cases  of  Malaria.  61 

infection  remain  stored  up  in  these  cells  than  that  they  should  exist 
for  such  a  length  of  time  free  in  the  circulation.  For  if  the  parasite 
is  capable  of  assuming  some  persistent  form  (crescentic  or  otherwise)/ 
it  is  scarcely  likely  that  such  a  form  could  long  be  retained  inactive 
in  the  intercellular  fluids,  since  it  would  almost  certainly  be  taken  up 
by  phagocytes.  Bastianelli  and  Bignami,  however,  combat  Golgi's 
idea  of  the  intra-cellular  development  of  the  parasites.  There  are 
many  examples  of  latent  bacterial  infections,  and  the  resistance  of 
certain  bacterial  forms  to  the  intra-cellular  digestion  is  generally 
appreciated  (cf.  the  researches  of  Wyssokowitch,  MetschnikoflP,  et  ai). 
For  the  present,  however,  it  must  be  granted  that  we  do  not  fully 
understand  all  the  conditions  which  underlie  latent  infection. 

Among  the  more  interesting  of  the  observations  on  phagocytosis  in 
malaria  are  those  dealing  with  the  inclusion  of  certain  phagocytes  by 
other  phagocytes — sometimes  of  phagocyte  by  phagocyte  even  to  the 
third  degree.  As  has  been  stated,  the  including  cell  sometimes 
looks  necrotic,  while  in  other  instances  it  is  the  included  cell  which 
shows  degenerative  changes ;  occasionally  both  cells  yield  normal 
staining  reactions.  That  such  inclusions  are  not  infrequent  the  sections 
from  the  fatal  cases  described  in  this  report  indisputably  prove.  Any 
attempt  at  explanation  must  be  speculative.  We  can  conceive  of 
active  small  cells  being  attracted  to  the  degenerating  protoplasm  of  a 
large  cell.  This  might  explain  the  instances  where  the  including  cell 
looked  degenerated.  Or  we  can  imagine  the  makrophage  taking  into 
its  substance  an  enfeebled  small  phagocyte,  in  which  case  the  included 
cell  will  be  degenerated.  Finally  we  can  conceive  of  a  small  active 
phagocyte  being  attracted  to  a  large,  more  sluggish  phagocyte  by  the 
masses  of  food  stuff  (broken  down  red  corpuscles,  etc.)  contained 
within  the  latter.  A  consideration  at  the  present  time  of  such  canni- 
balistic and  thieving  tendencies  on  the  part  of  the  white  cells  would 
lead  us  too  far  afield,  but  such  studies  are  among  the  many  attractive 
problems  connected  with  the  sociology  of  cells,  which,  it  is  to  be  hoped, 
the  physiologists  will  work  out  in  the  near  future. 


^  As  Bignami  points  out,  it  is  evident  that  some  explanation  other  than  the  re- 
sistance of  crescents  is  necessary  to  account  for  the  obstinacy  of  certain  tertian  and 
quartan  infections. 


DESCRIPTION    OF   PLATES. 


PLATE  in. 


Case  C. — Liver — showing  an  accumulation  of  small  round  mononuclear  cells  in 
a  portal  space. 

PLATE  IV. 

Case  C. — Liver — stained  with  haematoxylin  and  eosin — showing  an  area  of 
necrosis  with  accumulation  of  leucocytes,  many  of  which  have  distorted  nuclei. 
Fine  particles  of  malarial  pigment  may  be  seen  within  the  endothelial  cells  of  the 
capillaries  and  within  some  of  the  leucocytes. 

Near  the  lower  angle  of  the  drawing  a  small  thrombus  containing  numerous 
leucocytes  is  visible. 

PLATE  V. 

Case  C. — Liver ;  haematoxylin  and  eosin ;  high  power. 

Fig.  1. — Hyaline  thrombosis  of  an  hepatic  capillary;  accumulation  of  leucocytes; 
nuclear  distortion  ;  a  little  malarial  pigment  present. 

Fig.  2. — Thrombosis  of  adjacent  capillaries;  disappearance  of  intervening  liver 
cells ;  leucocytic  accumulation  ;  distortion  and  fragmentation  of  nuclei. 


PLATE  VI. 

Case  D. — Spleen  in  mixed  malarial  and  streptococus  infection.  Tissue  hardened 
in  alcohol ;  section  stained  in  methylene  blue  ;  accumulation  of  parasites  and  cocci 
within  the  vessels.  Many  of  the  malarial  parasites  have  been  absorbed  by  phago- 
cytes. In  the  lower  angle  of  the  large  vessel  to  the  right  a  large  mononuclear 
leucocyte  is  visible  which  contains  four  parasites.  Occasionally  cocci  and  malarial 
parasites  are  to  be  seen,  inside  the  same  phagocyte. 

The  makrophages  in  the  splenic  pulp,  some  containing  coarse  clumps,  others  finer 
particles  of  malarial  pigment,  are  numerous. 

Inside  the  vessels  the  makrophages  are  quite  like  those  described  within  the 
hepatic  capillaries  of  this  case. 

Some  of  the  endothelial  cells  contain  malarial  pigment  within  their  protoplasm. 

A  blue-stained  non-pigmented  sphere  within  the  malarial  parasite  is  well  shown 
in  several  parts  of  the  drawing. 

63 


The  Johns  Hopkins  Hospital  Reports. 


Vol.V.  Plate  in. 


MaxBredel.ffic 


IithAnst.yE  AFunk, Leipzig 


The  Johns  Hopkins  Hospital  Reports .  Vol .  V.  Plate  IV. 


e»    "=>    ^  •'03         (^^       ^°''oi,<*.'"°-=      rf)     -^      o 


© 


"r-     ' 


o<r 


'.  -i-«o 


^   Pi^"^3/b    .^v-^  « %    "'^ 


■j 


'^^ 


C-»°.-J   it-- A. 


r^ 


M.TBrodel  fee 


LitkAnstyE.AFunkeXcipziJ. 


The  Johns  Hopkins  Hospital  Reports . 


Vol. V.  Plate  V. 


Fig.  1. 


•Me 


'^3    O 


^^^^^^^ 


• 


r\ 


3 


Jf- 


Fi(j.  ?. 


i 


'  m  ma 


•^ 


^m^ 
-^^ 


^^ 


'y^m 


® 


1% 


M  Brodel  fer 


lith.  Ans  t  v.E.  AFunlce,  leip^i  J 


The  Johns Hop"kins  Hospital  Reports. 


Vol  .Y.  Plate  \1 


# 


Ti!       "5^ 


%»ff 


-i../"^^  /  ■"•^^^ 


-•  im^^^i'-'^^W  ^-/^'^^^^  '•:m^mm^^:: 


^'  ^c**  :%^  :t^^  #f;.Jrt  v=^* 


.;^a 


8 


M.Brodel  fee 


.AFunki;, 


'•'BRARY 


'"  ^-^^  cry  oj?  "°^'''^'". 


UBRARY 

OP  The 

PATHOLOGICAL    LABORAtOftY, 

TH^   PRESBYTERIAN    HOSPITAL 

IN  THE  CITY  OF  NEW  YORK. 


P     COLUMBIA  UNIVERSITY  LIBRARIES 

1^       This  book  is  due  on  the  date  indicated  below,  or  at  the 
p^   expiration  of  a  definite  period  after  the  date  of  borrowing,  as 
^^   provided  by  the  rules  of  the  Library  or  by  special  arrange- 
^^   ment  with  the  Librarian  in  charge. 

1 

^ 

IK^^     DATE  BORROWED 

DATE  DUE 

DATE  BORROWED 

DATE  DUE 

^ 

m 

^ 

m 

P 

§ 

m 

m 

M 

P 

W. 

M 

m 

m 

P 

i2^?    c2a(n4i)Mioo 

tVTJMT  ■«. 

i.aT<-\  •Mi**5T7N-::>C'i>iSC. 

TTt- JCTTJi>«  ".TJT-H-'rS 

'•■? 

■^■^^-ci 


fe 


/^d/^4 


B24 


^^Y 


